Progestins and antiprogestins

Definitions & Key takeaways

Progestins are synthetic that mimic the effects of progesterone, a hormone that plays a role in the menstrual cycle and pregnancy. Common uses of progestins include hormonal contraception (either alone or with estrogen), and prevention of endometrial hyperplasia from unopposed estrogen in hormone replacement therapy. Progestins are also used to treat secondary amenorrhea, dysfunctional uterine bleeding, endometriosis, and breast cancer. On the other hand, antiprogestins are drugs that block the effects of progesterone. Antiprogestins are used in pregnancy termination and emergency contraception.

Chapters:

Watch video only

Introduction0:00–0:39

Progestins are a group of synthetic progestogens that have similar effects to those of natural progesterone. They can be divided into two categories: the progesterone derivatives and the testosterone derivatives.
They are mainly used as contraceptives, in hormone replacement therapy, or HRT, and in the treatment of various gynecologic conditions.
Now, antiprogestins act as progesterone antagonists and include mifepristone and ulipristal. Mifepristone is used for medical abortion while ulipristal is used as an emergency contraceptive.

Physiology0:39–2:49

The hypothalamus 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.
During the two weeks following ovulation, which is referred to as the ovarian luteal phase, the remnant of the ovarian follicle becomes the corpus luteum, which is made up of luteinized theca and granulosa cells, meaning that these cells have been exposed to the high luteinizing hormone levels that occur just before ovulation.
The luteinized cells secrete more progesterone than estrogen and progesterone becomes the dominant hormone. Under the influence of progesterone, the uterus enters into the secretory phase of the endometrial cycle.
During this time, spiral arteries continue to grow, and the endometrial glands continue to produce more secretions that make the endometrium more receptive to the implantation of a fertilized gamete.
After day 15 of the cycle, the optimal window for fertilization begins to close and the corpus luteum gradually degenerates into the nonfunctional corpus albicans.
The corpus albicans doesn’t make hormones, so estrogen and progesterone levels slowly decrease. When progesterone reaches its lowest level, the spiral arteries collapse and the functional layer of the endometrium prepares to shed during menstruation.
This shedding marks the beginning of a new menstrual cycle and another opportunity for fertilization. Alright, apart from the female sex organs, progesterone also plays a role in bone strength, as well as keeping the skin elastic.
Also, during pregnancy, the placenta takes over progesterone secretion, which is required to maintain the pregnancy and also helps prepare the breasts for lactation after delivery.
But after menopause, the ovaries run out of functional ovarian follicles. So there’s no theca or granulosa cells to produce any more hormones, which accounts for many of the symptoms preceding menopause, like hot flashes, night sweats, vaginal atrophy, and osteoporosis.

Progestins2:49–4:12

Okay, now progestogens in general are a class of steroid hormones that bind to and activate the progesterone receptor. Once they’re inside the cells, they bind to progesterone receptors found in the cytoplasm, and together they form a complex that can travel into the nucleus and bind to progesterone-related genes, modifying the gene expression.
Synthetic progestogens, which are also called progestins are divided into two groups: the progesterone derivatives and the testosterone derivatives.
The progesterone derivatives include medroxyprogesterone, hydroxyprogesterone, and megestrol acetate. Now, the testosterone derivatives are basically derivatives of 19-nortestosterone and differ primarily in the degree of androgenic effects.
The older testosterone derivatives like danazol norgestrel, levonorgestrel, and ethynodiol are more androgenic than the newer testosterone derivatives such as desogestrel, norgestimate, and etonogestrel.
Progestins in general decrease growth and increase vascularization of the endometrium, and also thickens the cervical mucus.
While they are able to stabilize the endometrium, they can’t support pregnancy effectively like endogenous progesterone does.

Indications4:12–6:49

Okay, let’s move on to indications that are common for all progestins. They can be used as contraceptives, or birth control, either alone or in combination with an estrogen.
They can be administered orally, intramuscularly, through an intrauterine device, or a transdermal implant. They can also be used in combination with estrogen in hormone replacement therapy after menopause, in women with an intact uterus to prevent endometrial hyperplasia or endometrial cancer.
Even though transitioning into menopause is a natural step in the aging of the female reproductive system, the postmenopausal symptoms may have a negative impact on overall well-being.
So in some cases, hormone replacement therapy with estrogens are used to relieve symptoms. But all women with an intact uterus need progesterone in addition to estrogen in order to counteract the proliferative effects of estrogen to the endometrium, and prevent endometrial hyperplasia and endometrial cancer.
However, women who have undergone hysterectomy should not receive a progestin, because its key benefit is prevention of endometrial hyperplasia and carcinoma, and that’s no longer relevant.
Progestins can also be used in the diagnosis and treatment of various gynecological conditions such as: secondary amenorrhea, which is when a female who previously had menstrual periods suddenly stopped having them for at least 3 months; dysfunctional or abnormal uterine bleeding, which is when vaginal bleeding occurs outside of the regular menstrual cycle; and endometriosis, which is when cells of the endometrium grow outside the uterus.
In amenorrhea for example, individuals might have intrauterine adhesions, or Asherman syndrome. This is when there is scar tissue inside the uterine cavity, typically in a female who has undergone uterine instrumentation in the past, like dilation and curettage.
To assess uterine function a 10-day medroxyprogesterone test is done, which is called a progestin challenge, or progesterone withdrawal test.
That’s where 10 milligrams of medroxyprogesterone is given daily for 10 days, to see if that induces menstrual bleeding.
A healthy uterus should bleed. If there’s no bleeding, then estrogen is given to thicken the uterine lining, and medroxyprogesterone is added.
Failure to bleed strongly suggests endometrial scarring. Okay, another indication of progestins is endometrial carcinoma, or endometrial cancer, which is when malignant or cancer cells arise in the glands of the endometrium.

Side effects6:49–7:55

Alright, now for side effects. The toxicity of progestins is low at typical doses.
However, they may cause fluid retention and increase blood pressure, fatigue, mood changes and depression, breast discomfort, changes in libido, and menstrual irregularities such as breakthrough bleeding, which refers to any form of vaginal bleeding, usually mid-cycle.
Progestins, given in high doses for a long period of time, can also cause a reversible decrease in bone density, and delay the resumption of ovulation after termination of the therapy.
Now, older testosterone derivatives like norethisterone are more likely to cause virilization with symptoms like acne, hirsutism, voice deepening, and seborrhea, which is the excessive discharge of sebum from the sebaceous glands.
On the other hand, newer testosterone derivatives like desogestrel do not cause these side effects but they are associated with higher risk of venous thromboembolic disease.

Antiprogestins7:55–9:13

So let’s switch gears now and move on to antiprogestins, which include medications like mifepristone and ulipristal. Antiprogestins in general act as competitive inhibitors of progestins at progesterone receptors.
Mifepristone is given orally in combination with a prostaglandin analogue, such as misoprostol or gemeprost, because it can sensitize the uterus to the action of prostaglandins.
This combination is used as a medical alternative, called medical abortion, to surgical termination of pregnancy and it’s more than 95% effective during the first 50 days of pregnancy.
Side effects include gastrointestinal disturbances like nausea, vomiting, and diarrhea, vaginal bleeding due to the termination of the pregnancy, and rarely, serious infection, sepsis and even death caused by an atypical infection, such as Clostridium sordellii.
Now, ulipristal is used for emergency birth control, or emergency contraception, within 5 days or 120 hours after unprotected sexual intercourse.
Side effects include headache, tiredness, and gastrointestinal disturbances. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about progestins and antiprogestins.

Memory Palace9:13–11:26

Okay, so let’s set the scene at a park. On one side, there is a man and a woman holding hands.
They both wear a polo shirt to represent progestins. The woman represents progesterone derivatives, while the man represents testosterone derivatives.
For indications, they are talking to a giant condom mascot to help you remember progestins are used as contraceptives. By his feet, there’s a large uterus being pinched by a crab, since progestins can both prevent and treat endometrial cancer.
The crab is sweating and fanning itself since these drugs also relieve the symptoms of menopause. Finally behind the mascot, there’s a detective investigating a trash can with a bleeding uterus covered in weird lumps.
He should help you remember that progestins can help diagnose endometriosis and abnormal uterine bleeding. There’s also a box of tampons in the trash with the number “2” so progestins are also used to identify the cause of secondary amenorrhea.
For side effects, let’s have the man and woman holding hands with a happy little uterus who’s bleeding. And it also has shaky, boney legs to represent osteoporosis.
Now, these side effects are common in both the progesterone and testosterone derivatives. Okay, next let’s give the man a lot of acne since the older testosterone derivative progestins can cause virilization.
His leg is swollen with a bulging purple vein since the newer testosterone derivative progestins increase the risk of thrombosis.
Now let’s move onto the other side of the park which has a big sign that says, “no polo shirts,” and this is where we’ll put our antiprogestins.
There’s a terminator like robot here, to help you remember these antiprogestins are mainly used to terminate pregnancies.
He’s covered in patches of blood and bacteria to help you remember the complications like infections and uterine bleeding.
Finally, he’s also holding his stomach, representing the GI disturbances. All right, as a quick recap… Progestins are a class of medications that include progesterone derivatives and testosterone derivatives.

Review11:26–12:08

They bind to and activate the progesterone receptor, meaning that they have similar effects to those of natural progesterone.
Progestins are primarily used as contraceptives, as hormone replacement therapy, and to prevent and treat endometrial cancer.
Antiprogestins, like mifepristone and ulipristal, compete with progestins at progesterone receptors. Mifepristone, combined with a prostaglandin analogue, is used to terminate pregnancy, while ulipristal is used in emergency contraception.

Mind Map12:08–12:33

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.