Introduction to the Reproductive System: Physiology

Question 1

Introduction

Answer 1

a. The physiology of the male and female reproductive system consists of and can be conceptualized as the hypothalamic-pituitary-gonadal axis.

b. This axis has its function the production of mature gametes as well as the biosynthesis of various steroid hormones.
i. These sex steroids, in turn, exert effects in target tissues throughout the body.

c. Features of the biochemistry and physiology of this system emphasized in this session include:
i. The anterior pituitary secretes 2 hormones in response to hypothalamic stimulation: FSH and LH
ii. Some elements of the hypothalamic-pituitary-gonadal axis are the same in males and females, and some elements differ
iii. There are three major categories of sex steroids: progestins, androgens, and estrogens
iv. The production of sex steroids by the gonads relies on a coordinated system involving 2 cell types
v. Sex steroid production involves a progressive reduction in the number of carbon atoms
vi .Various sex steroids are produced in extra-gonadal tissues including the placenta, the dermis, the adrenal glands, and adipose tissue.

Question 2

Features of the biochemistry and physiology of this system emphasized in this session include:

Answer 2

a. The anterior pituitary secretes 2 hormones in response to hypothalamic stimulation: FSH and LH
b. Some elements of the hypothalamic-pituitary-gonadal axis are the same in males and females, and some elements differ
c. There are three major categories of sex steroids: progestins, androgens, and estrogens
d. The production of sex steroids by the gonads relies on a coordinated system involving 2 cell types
e. Sex steroid production involves a progressive reduction in the number of carbon atoms
f. Various sex steroids are produced in extra-gonadal tissues including the placenta, the dermis, the adrenal glands, and adipose tissue.

Question 3

Steroid Hormones

Key Features

Answer 3

a. The major classes of steroid hormones are glucocortocoids, mineralocorticoids, and sex steroids
b. The three major classes of sex steroids are progestins, androgens, and estrogens.
c. The conversion of cholesterol into the three major classes of sex steroids follows a progressive reduction in the number of carbon atoms the molecules contain.
d. Principle sources of sex steroids include the gonads, the adrenal cortex, and the placenta.
e. Peripheral tissues such as the skin, liver and adipose tissues play key roles in the conversion and metabolism of sex steroids.
f. The total amounts, relative amounts, and physiologic sources of circulating sex steroids differ between males and females.
g. The amounts of circulating estrogen and progesterone in women of reproductive age follow a monthly pattern, producing the changes in the endometrial lining of the uterus which lead to menstruation

Question 4

There are three major classes of steroid hormones

Answer 4

a. These include the glucocortocoids such as cortisol (C-21), the mineralocorticoids such as aldosterone (C-21), and the sex steroids which include progestins (C-21), androgens (C-19), and estrogens (C-18).
b. Like the bile salts and Vitamin D, all three major classes of steroid hormones have cholesterol as their precursor.
c. Cholesterol is a 27-carbon steroid molecule, with all 27 carbon atoms derived from acetyl-CoA in a series of steps beyond the scope of this session.

d. The biochemical relationships among the three major classes of steroid hormones is also addressed elsewhere.
i. three classes= glucocorticoid, mineralocorticoid, and sex steroids

Question 5

Creation of the Sex Steroids

Answer 5

a. Specific gonadal cells can synthesis cholesterol de novo from co-enzyme A or derive cholesterol from low-density lipoproteins (LDL’s) in the circulation.
b. Sex steroids can be produced in the gonads as well as in extra-gonadal tissues such as the adrenal cortex, the skin, and adipose tissue.
c. By a process which includes a reduction in the size of the hydrocarbon side-chain and hydroxylation of the 4-ring steroid nucleus, the cholesterol molecule is converted into the steroid hormones.

d. The initial and rate-limiting step in these reactions is catalyzed by the cholesterol side chain cleavage enzyme located in the mitochondrial membrane.
i. This enzyme is also known as 20, 22 desmolase.
ii. The resulting structure is a 21-carbon compound known as pregnenolone.

e. Pregnenolone is then converted into all other sex steroids.

Question 6

How Steroid is made from cholesterol

Answer 6

a. By a process which includes a reduction in the size of the hydrocarbon side-chain and hydroxylation of the 4-ring steroid nucleus, the cholesterol molecule is converted into the steroid hormones.

b. The initial and rate-limiting step in these reactions is catalyzed by the cholesterol side chain cleavage enzyme located in the mitochondrial membrane.
i. This enzyme is also known as 20, 22 desmolase.
ii. The resulting structure is a 21-carbon compound known as pregnenolone.

c. Pregnenolone is then converted into all other sex steroids.

Question 7

Progestins

Large Summary

Answer 7

a. Progestins are the 21-carbon sex steroids derived from cholesterol.
i. The progestins synthesized in the human body include pregnenolone, 17-alpha-hydroxy-pregnenolone, progesterone, and 17-alpha-hydroxy-progesterone (17-OH-P).

b. In addition to being sex steroids, progestins are also precursors for the production of aldosterone and cortisol by the adrenal gland.
i. Like progesterone, cortisol and aldosterone also have 21 carbons.

c. The major circulating progestins are progesterone and 17-hydroxy-progesterone, with the former present in higher concentrations in females.
d. Clinically, 17-hydroxy-progesterone is an excellent marker for late-onset congenital adrenal hyperplasia, which is discussed in other lectures.
e. Progestins affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts.

f. Key functions of progesterone include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation.
i. Progesterone levels fluctuate during the normal menstrual cycle.

g. Within the context of the hypothalamic – pituitary – ovarian axis, progesterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.

Question 8

Progestin Physiology

Answer 8

a. Progestins affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts.

b. Key functions of progesterone include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation.
i. Progesterone levels fluctuate during the normal menstrual cycle.

c. Within the context of the hypothalamic – pituitary – ovarian axis, progesterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.

Question 9

Progestin as precursors

Answer 9

a. In addition to being sex steroids, progestins are also precursors for the production of aldosterone and cortisol by the adrenal gland.
b. Like progesterone, cortisol and aldosterone also have 21 carbons.

Question 10

Different Types of Progestin

Answer 10

a. Progestins are the 21-carbon sex steroids derived from cholesterol.
b. The progestins synthesized in the human body include pregnenolone, 17-alpha-hydroxy-pregnenolone, progesterone, and 17-alpha-hydroxy-progesterone (17-OH-P).

c. In addition to being sex steroids, progestins are also precursors for the production of aldosterone and cortisol by the adrenal gland.
i. Like progesterone, cortisol and aldosterone also have 21 carbons.

d. The major circulating progestins are progesterone and 17-hydroxy-progesterone, with the former present in higher concentrations in females.

Question 11

Androgens

Large summary

Answer 11

a. Androgens are the 19-carbon sex steroids derived from cholesterol via pregnenolone.
i. The major androgens synthesized in the human body include testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), and androstenedione.
ii. Approximately 95% of the testosterone which circulates in the male is produced in the testes.

b. The other major source of androgens is the adrenal cortex.
i. The majority of DHEA and conjugated DHEA-S is produced in the adrenal cortex and serves as an excellent marker of adrenal androgen activity.
ii. Physiologic levels of adrenal androgens do not appear to have significant effects on the growth of the reproductive system.

c. Within the ovary, androstenedione from the Theca calls is the precursor for ovarian estradiol production by the granulosa cells.
i. Androstenedione is also a precursor for extraglandular estrogen formation in the liver and adipose tissues

d. 5-alpha-reductase is the enzyme which converts testosterone to dihydrotestosterone (DHT) in target cells such as those located in the prostate and skin.
i. The biologic activity of dihydrotestosterone (DHT) is 30 to 50 times higher than that of testosterone.
ii. Dihydrotestosterone cannot be converted to estrogens.

e. Testosterone affects almost all tissues in the body.
i. The effects are classified into two major categories: androgenic and anabolic.
ii. Androgenic impacts include the growth and development of the internal and external genitalia, the development and maintenance of secondary sex characteristics, spermatogenesis, and sexual fantasies and libido.
iii. Anabolic effects can be summarized as the growth-promoting effects on somatic tissues such as bone and muscle.

Question 12

Testosterone physiologic function

type of androgen

Answer 12

Testosterone affects almost all tissues in the body.

a. The effects are classified into two major categories: androgenic and anabolic.
b. Androgenic impacts include the growth and development of the internal and external genitalia, the development and maintenance of secondary sex characteristics, spermatogenesis, and sexual fantasies and libido.
c. Sebum production is an androgen dependent process.
d. Anabolic effects can be summarized as the growth-promoting effects on somatic tissues such as bone and muscle.
e. Within the hypothalamic – pituitary – testicular axis, testosterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary. The levels of circulating testosterone in men are relatively stable throughout most of adulthood.

Question 13

Testosterone to Dihydrotestosterone (DHT)

Answer 13

a. 5-alpha-reductase is the enzyme which converts testosterone to dihydrotestosterone (DHT) in target cells such as those located in the prostate and skin.
b. The biologic activity of dihydrotestosterone (DHT) is 30 to 50 times higher than that of testosterone.
c. Dihydrotestosterone cannot be converted to estrogens.

Question 14

Different Androgens within the body

Answer 14

a. Androgens are the 19-carbon sex steroids derived from cholesterol via pregnenolone.
b. The major androgens synthesized in the human body include testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), and androstenedione.
c. Approximately 95% of the testosterone which circulates in the male is produced in the testes.

d. The other major source of androgens is the adrenal cortex.
i. The majority of DHEA and conjugated DHEA-S is produced in the adrenal cortex and serves as an excellent marker of adrenal androgen activity.
ii. Physiologic levels of adrenal androgens do not appear to have significant effects on the growth of the reproductive system.

e. Within the ovary, androstenedione from the Theca calls is the precursor for ovarian estradiol production by the granulosa cells.
i. Androstenedione is also a precursor for extraglandular estrogen formation in the liver and adipose tissues

Question 15

Estrogens

Summary

Answer 15

a. Estrogens are the 18-carbon sex steroids derived from cholesterol via pregnenolone.
i. Pregnenolone is converted into other progestins, and then into the androgens.

b. Androgens are converted into the estrogens via an enzyme known as aromatase.
i. Aromatase is present in the gonads and in various peripheral tissues including adipose tissue, liver, ands the CNS.

c. The estrogens synthesized in the human body include estrone (E1), estradiol (E2) and estriol (E3).
i. They have one, two, and three hydroxyl groups, respectively.
ii. Of these, estradiol is the most potent and estriol is the least.
iii. Estradiol is the major circulating estrogen and is produced by the granulosa cells of the ovary in females and by the Sertoli cells of the testes in males.
iv. Estrone is derived from androstenedione in adipose tissue.
v. Estriol is an important placental product.

d. Estrogens affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts.
i. Key functions of estradiol include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation.
ii. Estradiol levels fluctuate during the normal menstrual cycle.
iii. Within the context of the hypothalamic – pituitary – ovarian axis, estradiol acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.

Question 16

Different types of Estrogen

Answer 16

a. The estrogens synthesized in the human body include estrone (E1), estradiol (E2) and estriol (E3).
i. They have one, two, and three hydroxyl groups, respectively.

b. Of these, estradiol is the most potent and estriol is the least.
c. Estradiol is the major circulating estrogen and is produced by the granulosa cells of the ovary in females and by the Sertoli cells of the testes in males.
d. Estrone is derived from androstenedione in adipose tissue.
e. Estriol is an important placental product.

Question 17

Estrogen Physiologic Effect

Answer 17

a. Estrogens affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts.
b. Key functions of estradiol include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation.
c. Estradiol levels fluctuate during the normal menstrual cycle.
d. Within the context of the hypothalamic – pituitary – ovarian axis, estradiol acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.

Question 18

Creation of Estrogen

Answer 18

a. Estrogens are the 18-carbon sex steroids derived from cholesterol via pregnenolone.
i. Pregnenolone is converted into other progestins, and then into the androgens.

b. Androgens are converted into the estrogens via an enzyme known as aromatase.
i. Aromatase is present in the gonads and in various peripheral tissues including adipose tissue, liver, ands the CNS.

c. The estrogens synthesized in the human body include estrone (E1), estradiol (E2) and estriol (E3).

Question 19

Sex Steroid Transport and action on cells

Answer 19

a. Sex steroids are hydrophobic and therefore carried in the bloodstream predominantly bound to plasma proteins.

b. These proteins include albumin, sex hormone binding globulin (SHBG), and corticosteroid binding globulin (CBG).
i. SHBG is produced in the liver.

c. Orally administered exogenous estrogens stimulate hepatic synthesis of SHBG.
i. Sex steroid molecules enter target cells via passive diffusion.

d. Testosterone and estradiol act on their target cells by binding to receptors located within the nucleus.
i. The gene encoding for the androgen receptor is located on the X chromosome. These activated sex steroid / receptor complexes then bind to nuclear chromatin, increasing the transcription of target proteins

Question 20

Hypothalamic- Pituitary-Gonadal Axis

Answer 20

a. Much like the adrenal and thyroid systems, the endocrine component of the reproductive system is organized around a hypothalamic – pituitary – endocrine organ axis.
b. In the male, this is called the hypothalamic – pituitary – testicular axis.
c. In females it is called the hypothalamic – pituitary – ovarian axis.

d. Key concepts of these axes include the role of inhibitory and stimulatory feedback loops, and, within the gonads, the 2 cell theory of sex hormone biosynthesis.
i. These axes provide a useful framework for understanding the physiology, the pathophysiology, and the pharmacology of the reproductive system.

Question 21

Hypothalamus and GnRH

Answer 21

a. The hypothalamus releases a compound called gonadotropin releasing hormone (GnRH) into the portal circulation, which delivers GnRH to the anterior pituitary gland.
b. Most of the GnRH originates in neurons of the arcuate nucleus and preoptic area of the hypothalamus.

c. GnRH is released into the portal circulation in a pulsatile fashion.
i. Pulsatility is key to the physiologic stimulation of the anterior pituitary as constant administration of GnRH actually suppresses the pituitary response.
ii. In adult males, approximately 8-14 pulses are released every 24 hours.

d. In adult females, patterns of GnRH, FSH, and LH secretion vary throughout the menstrual cycle.

Question 22

Anterior Pituitary and its release of FSH and LH

Answer 22

a. Within the anterior pituitary, GnRH stimulates responsive cells in the anterior pituitary to release Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH).

b. Though named for their functions in the female, LH and FSH are the primary regulators of gonadal function in both sexes.
i. Biochemically, they are related to TSH and Human Chorionic Gonadotropin (hCG). The alpha subunits of LH, FSH, hCG and TSH are identical.
ii. The beta subunits are distinct and confer specific functional and immunologic characteristics to the intact molecule.

c. Patterns of FSH and LH secretion change over the life cycle.
i. In ovulatory women, the levels of FSH and LH also vary throughout the menstrual cycle, reaching their peaks shortly before ovulation.
ii. The levels of circulating estradiol and progesterone produced in response to the FSH and LH also fluctuate in a cyclic pattern.
iii. The endometrial cells which form the uterine lining responds to these fluctuations in a predictable pattern which culminates in menstrual blood flow.

Question 23

Stimulation and Regulation of FSH/LH

Answer 23

a. To stimulate FSH and LH secretion by the pituitary gonadotrophs, GnRH binds to receptors on the cell surface.
i. LH and FSH are then released into the circulation and stimulate the production of sex steroids and inhibin.

b. The sex steroids exert negative feedback control on the reproductive axis at both the hypothalamic and pituitary levels.
c. Inhibin exerts negative feedback control on the reproductive axis exclusively at the level of the pituitary.
d. At midcycle in ovulatory women, ovarian estradiol also exerts positive feedback on the pituitary gland, leading to a surge in FSH and LH.

Question 24

In both sexes, gonadal sex steroid production and gametogenesis involve 2 distinct cell types working synergistically

Answer 24

a. In the testis, these are the Leydig and Sertoli cells.

b. In the ovary, they are the theca and the granulosa cells.
i. The theca and granulosa cells are located at the surface of the ovary in a layer known as the ovarian cortex.

c. Both cell types are required to metabolize cholesterol into estradiol, which is the principle gonadal estrogen.

Question 25

Comparing the 2 sex cell types on male and female

Answer 25

a. The male Leydig and female theca cells are interstitial cells and have many features in common.
i. These include the presence of LH receptors, the ability to make androgens, and the inability to make estrogens due to the absence of aromatase.

b. The male Sertoli and female granulosa cells are immediately adjacent to the developing gametes and also have many features in common.
i. These include the presence of FSH receptors, the ability to make inhibin, and the ability to convert androgens into estrogens due to the presence of aromatase.

Question 26

The Leydig Cells

Answer 26

a. The Leydig cells occupy the interstitial layer surrounding the seminiferous tubules.
b. In response to LH, Leydig cells produce around 95% of the testosterone in males.

c. LH stimulates the rate-limiting conversion of cholesterol into pregnenolone in two ways:
i. by increasing the amount of desmolase
and
ii. by enhancing the affinity of desmolase for cholesterol.

d. The resulting testosterone which acts on the Sertoli cells to support spermatogenesis.
i. This testosterone also exerts negative feedback on the hypothalamic – pituitary – testicular axis at both the hypothalamic and pituitary levels.

Question 27

The Sertoli Cells

Answer 27

a. The Sertoli cells in the male are in direct contact with the developing spermatozoa and are regarded as the as the support or nurse cells of the developing spermatozoa.
b. Spermatogenesis requires LH, FSH, Leydig cells, Sertoli cells, and testosterone.

c. The Sertoli cells are organized into a tubular epithelium known as the seminiferous tubule.
i. This general structure is supported by the presence of tight gap junctions between adjacent Sertoli cells.

d. Maturing spermatogonia are located between adjacent Sertoli Cells. Gap junctions between Sertoli cells and the adjacent spermatozoa are responsible for the maturation of those gametes.

Question 28

FSH binding to Sertoli cells

Answer 28

FSH binding to Sertoli cells has several effects.

a. These include increased production of androgen binding protein, enhanced conversion of testosterone from the Leydig cells into estradiol, and the production of inhibin.

b. The Sertoli cells are the primary source of inhibin in males.
i. Inhibin plays an important role in the negative feedback arm of the hypothalamic-pituitary-testicular axis.

Question 29

The Theca Cells

Answer 29

a. The theca cells are located in the ovarian stroma surrounding the follicles and are similar to the Leydig cells in the male.
b. In response to LH secretion, theca cells produce progesterone and androgens.
c. Theca cells lack aromatase and therefore the capacity to produce estrogens.
d. Androstenedione from the theca cells must therefore diffuse into nearby granulosa cells for estrogen to be produced.

Question 30

The ovarian granulosa cells

Answer 30

a. The ovarian granulosa cells are in direct contact with the oogonia and are similar to the Sertoli cells in the male.

b. The gametes and their surrounding granulosa cells are called primordial follicles.
i. In reproductive age women, one follicle, called the dominant follicle, matures each month.

c. Oogenesis and ovulation require LH, FSH, granulosa cells, theca cells, testosterone and estradiol.
d. Granulosa cells lack the enzyme which converts progesterone into androgens.
e. Progesterone from the granulosa cells must therefore diffuse to the theca cells where it is converted into androstenedione.
f. As mentioned above, theca cells lack aromatase, so the resulting androstenedione diffuses back to the granulosa cells for conversion to estradiol

Question 31

Progestin Major Points

Answer 31

a. Progestins are the 21-carbon sex steroids derived from cholesterol.
b. The progestins synthesized in the human body include pregnenolone, 17-alpha-hydroxy-pregnenolone, progesterone, and 17-alpha-hydroxy-progesterone (17-OH-P).

c. In addition to being sex steroids, progestins are also precursors for the production of aldosterone and cortisol by the adrenal gland.
i. Like progesterone, cortisol and aldosterone also have 21 carbons.

d. The major circulating progestins are progesterone and 17-hydroxy-progesterone, with the former present in higher concentrations in females.
i. Clinically, 17-hydroxy-progesterone is an excellent marker for late-onset congenital adrenal hyperplasia, which is discussed in other lectures.

Question 32

Progestin- What different steroids it can become

Answer 32

1. Androgens are the 19-carbon sex steroids derived from cholesterol via pregnenolone.
   i. The major androgens synthesized in the human body include testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), and androstenedione.
   ii. Approximately 95% of the testosterone which circulates in the male is produced in the testes.
   iii. The other major source of androgens is the adrenal cortex.
2. Estrogens are the 18-carbon sex steroids derived from cholesterol via pregnenolone.
   i. Pregnenolone is converted into other progestins, and then into the androgens.
   ii. Androgens are converted into the estrogens via an enzyme known as aromatase.
   iii. The estrogens synthesized in the human body include estrone (E1), estradiol (E2) and estriol (E3). They have one, two, and three hydroxyl groups, respectively.
   iv. Of these, estradiol is the most potent and estriol is the least.
   v. Estradiol is the major circulating estrogen and is produced by the granulosa cells of the ovary in females and by the Sertoli cells of the testes in males

Question 33

Functions of Progestin, Androgen, and Estrogen

Answer 33

1. Progestins affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts.
   i. Key functions of progesterone include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation.
   ii. Progesterone levels fluctuate during the normal menstrual cycle.
   iii. Within the context of the hypothalamic – pituitary – ovarian axis, progesterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.
2. Androgens–>Testosterone affects almost all tissues in the body.
   i. The effects are classified into two major categories: androgenic and anabolic.
   ii. Androgenic impacts include the growth and development of the internal and external genitalia, the development and maintenance of secondary sex characteristics, spermatogenesis, and sexual fantasies and libido.
   iii. Anabolic effects can be summarized as the growth-promoting effects on somatic tissues such as bone and muscle.
   iv. Within the hypothalamic – pituitary – testicular axis, testosterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.
3. Estrogens affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts.
   i. Key functions of estradiol include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation.
   ii. Estradiol levels fluctuate during the normal menstrual cycle.
   iii. Within the context of the hypothalamic – pituitary – ovarian axis, estradiol acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.

Question 34

Sex Steroid Introduction

Answer 34

a. Sex steroids are steroid hormones that interact with vertebrate androgen or estrogen receptors.

b. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and signaling cascades.
i. The term sex hormone is nearly always synonymous with sex steroid.

c. In many contexts, the two main classes of sex steroids are androgens and estrogens, of which the most important human derivatives are testosterone and estradiol, respectively.
i. Other contexts will include progestogens as a third class of sex steroids, distinct from androgens and estrogens.
ii. Progesterone is the most important and only naturally-occurring human progestogen.

d. In general, androgens are considered “male sex hormones”, since they have masculinizing effects, while estrogens and progestogens are considered “female sex hormones” although all types are present in each sex, albeit at different levels.

Question 35

Androgen Wiki Summary

Answer 35

a. Androgen is any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors.

b. This includes the activity of the primary male sex organs and development of male secondary sex characteristics.
i. Androgens are also the original anabolic steroids and the precursor of all estrogens.

c. The primary and most well-known androgen is testosterone
i. Dihydrotestosterone (DHT) and androstenedione are less known generally, but are of equal importance in male development
ii. DHT in the embryo life causes differentiation of penis, scrotum and prostate.
iii. Later in life DHT contributes to male balding, prostate growth and sebaceous gland activity.

d. Although androgens are described as male sex hormones, both males and females have them to varying degrees, as is also true of estrogens.

Question 36

Know general structure and where Androgens are made

*Know this

Answer 36

The main subset of androgens, known as adrenal androgens, is composed of 19-carbon steroids synthesized in the zona reticularis, the innermost layer of the adrenal cortex.

Question 37

Types of Androgens

Wiki Great summary

Answer 37

a. The main subset of androgens, known as adrenal androgens, is composed of 19-carbon steroids synthesized in the zona reticularis, the innermost layer of the adrenal cortex.
b. Besides testosterone, other androgens include:

1) Dehydroepiandrosterone (DHEA) is a steroid hormone produced in the adrenal cortex from cholesterol.
i. It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.

2) Androstenedione (Andro) is an androgenic steroid produced by the testes, adrenal cortex, and ovaries.
3) Androstenediol is the steroid metabolite thought to act as the main regulator of gonadotropin secretion.
4) Dihydrotestosterone (DHT) is a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. It is produced in the skin and reproductive tissue.

Question 38

Estrogen Wiki Summary

Answer 38

a. Estrogen is the primary female sex hormone. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics.
b. The steroid 17β-estradiol is the most potent and prevalent endogenous estrogen, although several metabolites of estradiol also have estrogenic hormonal activity.

c. The three major naturally occurring forms of estrogen in women are estrone (E1), estradiol (E2), and estriol (E3).
i. Quantitatively, estrogens circulate at lower levels than androgens in both men and women

d. While estrogen levels are significantly lower in males compared to females, estrogens nevertheless also have important physiological roles in males.
e. Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors (ERs) which in turn modulate the expression of many genes

Question 39

The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3).

Answer 39

a. The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3).
b. Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity.
c. During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels.
d. Though estriol is the most plentiful of the three estrogens it is also the weakest, whereas estradiol is the strongest with a potency of approximately 80 times that of estriol.
e. Thus, estradiol is the most important estrogen in non-pregnant females who are between the menarche and menopause stages of life.

Question 40

Function of Progestogen

Answer 40

a. In the first step in the steroidogenic pathway, cholesterol is converted into pregnenolone (P5), which serves as the precursor to the progestogens progesterone and 17α-hydroxyprogesterone.
b. These progestogens, along with another steroid, 17α-hydroxypregnenolone, are the precursors of all other endogenous steroids, including the androgens, estrogens, glucocorticoids, mineralocorticoids, and neurosteroids.
c. Thus, many tissues producing steroids, including the adrenal glands, testes, and ovaries, produce progestogens.

d. All progestogens are characterized by their basic 21-carbon skeleton, called a pregnane skeleton (C21).
i. In similar manner, the estrogens possess an estrane skeleton (C18), and androgens, an andrane skeleton (C19).

Question 41

Carbon Skeletons for Progesteron, Androgen, and Estrogen

Answer 41

a. All progestogens are characterized by their basic 21-carbon skeleton, called a pregnane skeleton (C21).
b. In similar manner, the estrogens possess an estrane skeleton (C18), and androgens, an andrane skeleton (C19).

Question 42

Hypothalamic–pituitary–gonadal axis

Wiki Intro

Answer 42

a. The hypothalamic–pituitary–gonadal axis (HPG axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity.
i. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

b. The HPG axis plays a critical part in the development and regulation of a number of the body’s systems, such as the reproductive and immune systems.
i. Fluctuations in this axis cause changes in the hormones produced by each gland and have various local and systemic effects on the body.

c. The axis controls development, reproduction, and aging in animals.
i. Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus by GnRH-expressing neurons.
ii. The anterior portion of the pituitary gland produces luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and the gonads produce estrogen and testosterone.

d. The HPA, HPG, and HPT axes are three pathways in which the hypothalamus and pituitary direct neuroendocrine function.

Question 43

Hypothalamic–pituitary–gonadal axis

Regulation Wiki

Answer 43

a. The hypothalamus is located in the brain and secretes GnRH.
i. GnRH travels down the anterior portion of the pituitary via the hypophyseal portal system and binds to receptors on the secretory cells of the adenohypophysis.

b. In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.
i. These two hormones play an important role in communicating to the gonads.

c. In females FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin and to regulate the menstrual cycle and ovarian cycle.
i. Estrogen forms a negative feedback loop by inhibiting the production of GnRH in the hypothalamus.
ii. Inhibin acts to inhibit activin, which is a peripherally produced hormone that positively stimulates GnRH-producing cells.
iii. Follistatin, which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis.

d. In males LH stimulates the interstitial cells located in the testes to produce testosterone, and FSH plays a role in spermatogenesis.
i. Only small amounts of estrogen are secreted in males. Recent research has shown that a neurosteroid axis exists, which helps the cortex to regulate the hypothalamus’s production of GnRH

Question 44

GnRH for Females

Regulation

Answer 44

a. In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.
i. These two hormones play an important role in communicating to the gonads.

b. In females FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin and to regulate the menstrual cycle and ovarian cycle.
c. Estrogen forms a negative feedback loop by inhibiting the production of GnRH in the hypothalamus.

d. Inhibin acts to inhibit activin, which is a peripherally produced hormone that positively stimulates GnRH-producing cells.
i. Follistatin, which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis

Question 45

GnRH for Males

Regulation

Answer 45

a. In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.
i. These two hormones play an important role in communicating to the gonads.

b. In males LH stimulates the interstitial cells located in the testes to produce testosterone, and FSH plays a role in spermatogenesis.
c. Only small amounts of estrogen are secreted in males.
d. Recent research has shown that a neurosteroid axis exists, which helps the cortex to regulate the hypothalamus’s production of GnRH

Question 46

Leydig cell

Answer 46

a. Leydig cells are found adjacent to the seminiferous tubules in the testicle.
i. They produce testosterone in the presence of luteinizing hormone (LH).

b. Leydig cells release a class of hormones called androgens (19-carbon steroids).
c. They secrete testosterone, androstenedione and dehydroepiandrosterone (DHEA), when stimulated by the pituitary hormone luteinizing hormone (LH).
d. LH increases cholesterol desmolase activity (an enzyme associated with the conversion of cholesterol to pregnenolone), leading to testosterone synthesis and secretion by Leydig cells.
e. Prolactin (PRL) increases the response of Leydig cells to LH by increasing the number of LH receptors expressed on Leydig cells.

Question 47

Sertoli cell

Answer 47

a. A Sertoli cell is a “nurse” cell of the testicles that is part of a seminiferous tubule and helps in the process of spermatogenesis; that is, the production of sperm.

b. It is activated by follicle-stimulating hormone (FSH) secreted by the adenohypophysis, and has FSH receptor on its membranes.
i. It is specifically located in the convoluted seminiferous tubules (since this is the only place in the testes where the spermatozoa are produced).
ii. Development of Sertoli cells is directed by the testis-determining factor protein.

Question 48

Theca Cells

Answer 48

a. Theca cells are a group of endocrine cells in the ovary made up of connective tissue surrounding the follicle that has many diverse functions during folliculogenesis.
b. These roles include synthesizing androgens, providing signal transduction between granulosa cells and oocytes during development by the establishment of a vascular system, providing nutrients, and providing structure and support to the follicle as it matures.
c. The theca cells are responsible for the production of androstenedione, and indirectly the production of 17β estradiol, also called E2, by supplying the neighboring granulosa cells with androstenedione that with the help of the enzyme aromatase can be used as a substrate for this type of estradiol.
d. FSH induces the granulosa cells to make aromatase that converts the androgens made by the theca interna into estradiol.

Question 49

Granulosa Cells

The ovarian granulosa cells

Answer 49

a. A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals.
b. The major functions of granulosa cells include the production of sex steroids, as well as myriad growth factors thought to interact with the oocyte during its development.
c. The sex steroid production consists of follicle-stimulating hormone (FSH) stimulating granulosa cells to convert androgens (coming from the thecal cells) to estradiol by aromatase during the follicular phase of the menstrual cycle.
d. However, after ovulation the granulosa cells turn into granulosa lutein cells that produce progesterone.
e. The progesterone may maintain a potential pregnancy and causes production of a thick cervical mucus that inhibits sperm entry into the uterus.