Module 5 Section 3 (Gonadosteroids)

Question 1

What are gonadosteroids?

Answer 1

Gonadosteroids are hormones produced by the testes or ovaries that stimulate reproductive organs, germ cell maturation, and the secondary sex characteristics in males and females.

Question 2

What are the major sex hormones?

Answer 2

The major sex hormones in females are estrogens and progestins, while the major sex hormones in males are the androgens.

Question 3

What are the female sex hormones?

Answer 3

Estradiol is the major estrogen steroid hormone in females.

• It is an endogenously produced estrogen secreted mainly by the ovaries.
• It’s predominantly involved in the development and maintenance of the female sexual characteristics.

Progesterone is an endogenously produced progestin secreted by the corpus luteum and placenta that is involved with the maintenance of the ovarian cycle and pregnancy.

Semisynthetic and synthetic estrogens, progestins, anti-estrogens, and anti-progestins have all been developed as therapeutic agents.

Question 4

What are the female sex hormones?

Answer 4

Testosterone is an endogenously produced androgen secreted mainly by the testes (95%). Androgens function in the body to:

• regulate gene expression by activating nuclear receptors
• develop primary and secondary male sex characteristics
• mature sperm
• increase muscle mass (anabolic effect)

Question 5

Based on your previous knowledge of the reproductive system, what are some therapeutic implications of gonadosteroids? Hint: think about the types of conditions these drugs could be used to treat.

Answer 5

Therapeutic indications for modifying the actions of gonadosteroids includes (both agonists and antagonists):

• Hormonal contraception in females
• Hormone replacement therapy
• Transgender hormonal therapy
• Breast cancer treatment (e.g. selective estrogen receptor modulators and androgens)
• Prostate cancer (e.g. anti-androgens)
• Infertility treatment
• Menstrual disorders (e.g. menorrhagia, dysmenorrhea)
• Endometriosis
• Acne
• Anemia refractory to treatment: androgens stimulate erythropoiesis
• Anabolic agents: compensate for protein loss (e.g. after trauma, surgery, or prolonged immobilization). Often abused by body builders and athletes.

Question 6

Are the levels of estrogen and progesterone high or low at the start of the follicular phase? At the start of the luteal phase

Answer 6

1) The follicular phase begins with menstruation, where levels of estrogen and progesterone low.
2) In response to these low levels of hormones, LH and FSH are released, which causes ovarian follicles to develop and begin releasing estrogen.
3) By day 14, estrogen levels in the blood are high and the follicle will be released from the ovary - this is called ovulation.
4) After ovulation, you enter the luteal phase. Levels of LH, FSH, and estrogen in the blood decrease, while progesterone increases and prepares the uterus for implantation.

Question 7

The mechanism of action of all female hormonal contraceptives is essentially the same – they suppress the release of gonadotropins. How does this occue?

Answer 7

1) Administration of a hormonal contraceptive inhibits the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus in the brain.

2) GnRH stimulates the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH), thus there is decreased levels of these two hormones in circulation.
- As a result, there is no follicular maturation in the ovaries and ovulation is inhibited.

3) On top of these effects, progestins also alter the secretions of the endocervical gland to a scant, thick fluid not optimal for sperm migration.
- The endometrium is not fully developed and is, thus, unsuitable for implantation of a fertilized ovum.

Question 8

The term “oral contraceptive” usually refers to what?

Answer 8

The term “oral contraceptive” usually refers to a product containing both an estrogen and a progestin (progesterone-like compound).

Question 9

Which preparations of oral contraceptive are the most effective developed to date and also the most widely used?

Answer 9

1) Fixed Combinations: pills with a fixed combination of estrogen and a progestin.

2) Multiphasic: these usually contain a fixed amount of estrogen and variable amounts of progestin; the progestin increases from week to week.
- Currently the oral contraceptives of choice, more closely mimic the pattern of hormones released in the normal ovarian cycle.

3) Continuous: continuous estrogen-progestin preparations are taken for 28 days each cycle with no drug free period, eliminating menstruation.

4) Mini-pill: A daily dose of progestin is taken as long as the drug is needed.
- Patient acceptability is less than with the estrogen-progestin combinations, since breakthrough bleeding is often a problem.

Question 10

What are the adverse side effects of oral contraceptives?

Answer 10

Some of the serious adverse effects include:
- Blood clots: The risk of developing blood clots is increased from one per 100,000 women per year for non-users of the pill to three per 100,000 women per year for users.
• Heart attack: The estrogen-progestin oral contraceptives are associated with a small increased risk for heart attack. The risk is greater if the patient is obese, or if the patient smokes.
• Stroke: Women taking oral contraceptives have an increased risk for cerebrovascular disease (stroke). The risk is greater if the patient is over 35 years of age, but all ages are affected.

• Hypertension: Hypertension has been observed in women taking oral contraceptives. The exact risk of developing high blood pressure is not known, however it is believed to be caused by estrogen in the oral contraceptive. Hypertension as an adverse effect of oral contraceptives is more prevalent in women over 35 years of age.
• Cancer: Many studies have investigated the effect of oral contraceptives on cancer risk. The current consensus is that:
  • endometrial and ovarian cancer risks are reduced.
  • an increased risk of developing breast cancer is not apparent.
  • no clear decision has been made with respect to cervical cancer, as it is complicated by human papillomavirus infection

Question 11

Oral contraceptives can have benefits in some individuals that are unrelated to conception. List some examples.

Answer 11

• reduced risk of ovarian cysts
• reduced risk of ovarian and endometrial cancer
• reduced incidence of ectopic pregnancy
• less iron deficiency anemia, as menstrual flow is reduced
• less acne and hirsutism (for those containing newer progestins with less androgenic effect).

Question 12

Other types of hormonal contraceptives exist, but most of them are less commonly used. What are they?

Answer 12

1) Depo-Provera: an injectable progestin injected intramuscularly every three months, and thus provides contraception for about 3 months.
2) Transdermal contraceptive patch: these products contain ethinyl estradiol and norelgestromin (progestin) in a patch that is applied to the skin. The drug is delivered at a constant rate for 7 days, the time the patch is worn.
3) Norplant: this product is comprised of silicone tubes filled with L-norgestrel (a progestin) which are implanted under the skin. The drug is released over a period of five years and provides effective contraception during this time.
4) Vaginal contraceptive ring: the vaginal contraceptive ring is a 54 mm ring made of a copolymer that releases a constant dose of 15 μg ethinyl estradiol, and 0.120 mg of etonogestrel per day. The devise is placed in the vagina for 21 days of a 28-day cycle. A new ring is used each month.
5) Intra-uterine device (IUD) that releases levonorgestrel (a progestin): this device is implanted into the uterus by a medical professional and is effective for 5 years. IUDs are very effective and are becoming the contraceptive of choice for women who desire long-term contraception

Question 13

Fertility control methods also include post-coital contraceptives and termination of pregnancy (abortion). Discuss the pharmacology behind those drugs. Provide examples.

Answer 13

Estrogen: Post-coital contraceptives consist of large doses of estrogen that are taken usually within 24 hours, but no later than 72 hours after coitus.

• This form of emergency contraception may have several mechanisms of action, such as interfering with follicular development, altering cervical mucus, altering sperm migration, and inhibiting fertilization.
• The major problem with use of these drugs is the nausea caused by the estrogen.
• Examples are Preven and Plan B.

Antiprogestins: Anti-progesterones block the effect of the progesterone receptor in the endometrium. The endometrium then lacks the support of progesterone, bringing on menstruation.

• The drug can be taken after a missed period to bring on menstruation and initiate an early abortion.
• It is usually used with a prostaglandin that can induce uterine contractions.
• Ex: Mifegymiso is a new drug available since January 2017 that is a combination of an anti-progesterone and prostaglandin (i.e. mifepristone and misoprostol, respectively).

Question 14

True or false: gonadosteroids can also be used for hormone replacement therapy.

Answer 14

True

Hormone replacement therapy is used in a number of conditions in both females and males

Question 15

What is hypogonadism?

Answer 15

Hypogonadism is the reduction or absence of hormone secretion or other physiological activity of the gonads (testes or ovaries).

Question 16

Hypogonadism is different in males and females as they have different sex hormones. Discuss the differences (ex: treatment, adverse effects, etc).

Answer 16

Female hypogonadism: primary female hypogonadism is when the ovaries produce little or no estrogen, which can lead to delayed puberty.

• The aim of treatment is to mimic physiological levels of estrogen to stimulate the development of secondary sex characteristics and menses, to stimulate optimal growth, and to prevent osteoporosis.
• Treatment consists of small doses of estrogen on days one to 21 of each month (to mimic the ovarian cycle) and is usually started in females 11 to 13 years old.
• When growth is completed, therapy consists of administration of adult doses of both estrogens and progestins until the age when menopause normally occurs (around 52 years of age).

Male Hypogonadism: it can be a result of testicular failure (primary hypogonadism) or of hypothalamic-pituitary disease (secondary hypogonadism).

• Treatment for both primary and secondary hypogonadism is androgen (i.e. testosterone) replacement. The goal of treatment is to stimulate development of male secondary sex characteristics and to maintain muscle and bone mass.
• Common adverse effects are acne, sleep apnea, gynecomastia, and azoospermia (absence of viable sperm).

Postmenopausal Women: menopause is the term to signify the cessation of ovarian function and is characterized by loss of menstrual periods, sleep disturbance, flushing, headaches, and insomnia.
- However, menopause is also associated with longer-lasting changes, including acceleration of bone loss and lipid changes that may contribute to the acceleration of atherosclerotic cardiovascular disease.

Elderly Men: androgen production decreases with age in men, and may contribute to the decline in muscle mass, strength, and libido that occurs with aging.

• Preliminary studies of androgen replacement suggest that increasing serum testosterone will increase bone mineral density and lean mass, and decrease fat mass.
• However, it is uncertain whether androgen replacement will worsen benign prostatic hyperplasia or increase the incidence of prostate cancer.

Question 17

Management of postmenopausal women requires careful assessment of the symptoms as well as consideration of age and risk factors for osteoporosis, cardiovascular disease, breast cancer, and endometrial cancer. Discuss these risk factors

Answer 17

Bone density: estrogen replacement therapy has been shown to be effective in preventing the decrease in bone density occurring at menopause.

Cardiovascular disease: decreased levels of estrogen do result in an accelerated rise in plasma cholesterol and LDL concentrations, and estrogen replacement therapy has a beneficial effect on these circulating lipids.

• However, a large study from the Women’s Health Initiative showed no cardiovascular benefit from estrogen plus progestin replacement therapy.
• Overall, it has been determined that the increase in cardiovascular risk in postmenopausal women depends on the degree of atherosclerosis at the onset of menopause.

Cancer: the relation of estrogen therapy and cancer risk is a subject of active research. Many studies show an increased risk of endometrial carcinoma in patients taking estrogens alone, however, concomitant use of a progestin prevents this increased risk.

• Breast cancer incidence is not increased with short-term estrogen therapy.
• However, a small increase in incidence may occur with prolonged therapy and addition of progesterone is not protective in this case.
• Further studies are needed to determine the association between progestins and breast cancer risk.

Question 18

Hormone therapy may also be used in transgender individuals. What hormones are generally administered?

Answer 18

Transgender Women: the greatest heath concern for hormone therapy in transgender women is thromboembolic events, such as venous thromboembolism, cerebrovascular disease, and myocardial infarcts, as these events may be estrogen related.

• To minimize the risk of thromboembolic events occurring, transgender women (in partnership with their physician) should address any hypercholesterolemia, hypertension, or smoking use.
• Transgender women who have hypercoagulable disorders, or are immobilized, should also be closely monitored.
• A decrease in sexual desire may also be experienced by transgender women, due to the anti-androgens.

Transgender Men: hormone therapy appears to cause polycythemia (an elevation of the volume percentage of red blood cells).
- As such, blood profile monitoring is recommended.

Question 19

What are the adverse effects of hormone therapy?

Answer 19

Most studies indicate that both transgender men and women on hormone therapy experience elevated fasting glucose and increased insulin resistance, relating to increases in type 2 diabetes.

Larger, long-term studies are needed in transgender medicine to determine the long-term effect of hormone therapy on transgender individuals.

Question 20

True or false: a large study consisting of 2000 transgender adults from 15 different centers found no increase in mortality compared to controls due to transgender hormone therapy.

Answer 20

True

Current data suggests that hormone therapy is safe in transgender adults with close physician supervision for adverse effects.

Question 21

Hormone therapy also plays a role in cancer treatment. Discuss its role.

Answer 21

Tamoxifen is known as a selective estrogen receptor modulator, meaning that it is a compound that has tissue-selective actions.

• Tamoxifen is a competitive estrogen receptor blocker in breast and endometrial tissues, and it is used in the treatment of estrogen-sensitive breast cancer.
• Following unilateral excision of breast cancer, tamoxifen therapy reduces the risk of developing cancer in the second breast by 35%.
• Tamoxifen is also used for chemoprevention of breast cancer in high-risk women, and in the palliative treatment of breast cancer in postmenopausal women.

Androgens have also been used for chemotherapy of breast tumours in premenopausal women, while antiandrogens (e.g. cyproterone) can be used to treat prostate cancer.

Question 22

What is the treatment for infertility?

Answer 22

Clomiphene is considered an anti-estrogen, meaning it is an estrogen receptor antagonist in all tissues.

• It inhibits the estrogen-mediated negative feedback on the hypothalamus.
• It induces ovulation and is used in the treatment of infertility.
• The most common adverse effect experienced by clomiphene is hot flashes, which resemble those experienced by menopausal patients.

Question 23

Which group of people require very close monitoring while undergoing hormone therapy?

a) Transgender women with a coagulation disorder
b) Transgender men with a slightly low RBC count
c) Females with hypogonadism and high calcium levels
d) Males with hypogonadism and unrelated male pattern baldness

Answer 23

a) Transgender women with a coagulation disorder

Question 24

Which one of the options listed is a function of estrogen?

a) Increase muscle mass
b) Maintain uterus during pregnancy
c) Mature sperm
d) Develop primary and secondary female sex characteristics

Answer 24

d) Develop primary and secondary female sex characteristics