Introduction to the Reproductive System: Physiology Flashcards
Introduction
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.
Features of the biochemistry and physiology of this system emphasized in this session include:
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.
Steroid Hormones
Key Features
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
There are three major classes of steroid hormones
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
Creation of the Sex Steroids
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.
How Steroid is made from cholesterol
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.
Progestins
Large Summary
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.
Progestin Physiology
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.
Progestin as precursors
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.
Different Types of Progestin
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.
Androgens
Large summary
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.
Testosterone physiologic function
type of androgen
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.
Testosterone to Dihydrotestosterone (DHT)
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.
Different Androgens within the body
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
Estrogens
Summary
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.
Different types of Estrogen
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.
Estrogen Physiologic Effect
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.
Creation of Estrogen
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).
Sex Steroid Transport and action on cells
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
Hypothalamic- Pituitary-Gonadal Axis
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.
Hypothalamus and GnRH
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.
Anterior Pituitary and its release of FSH and LH
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.
Stimulation and Regulation of FSH/LH
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.
In both sexes, gonadal sex steroid production and gametogenesis involve 2 distinct cell types working synergistically
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.