Pharmacology of Reproduction Flashcards
Developing as a male or female
- A complex series of events triggered by sex chromosomes (XX vs. XY).
- Outside the gonads, male and female is mainly dependent upon levels of androgen hormones…
- Bi-potential organ precursors develop into male-specific (testosterone high) or female-specific (testosterone low) organs.
- Organs stay the same 30-40 days after conception-the the first hormonal surge comes and changes in gene expression actually determine male or female.
- Presence of a Y chromosome triggers male gonad development; testosterone and its metabolites trigger male-specific development outside the gonad.
- SRY gene on the male Y chromosome; when expression in Sertoli cells, triggers secretion of anti-Mullerian hormone, which is secreted from the Sertoli cells and causes regression of the Mullein ducts (develop into female anatomy).
- Simultaneously when the SRY gene is expressed in the Sertoli cells, the Leydig cells start to secrete testosterone and you get male-specific development (wolfing-duct development)
- Do not need any hormone signaling to develop as female.
- Female development is the DEFAULT path and does not require female hormones until puberty; occurs in the absence of androgens; Mullerian ducts develop and the Wolffian ducts degenerate.
- Male anatomical development depends on the androgen, testosterone, and its metabolites (DHT).
- It is important for women to avoid exposure to drugs that modify androgen signaling (especially during pregnancy); this could disrupt the gender development of the embryo in utero and into adulthood.
Anatomy and Histology-Males
-Testis
Site of reproductive cells and male sex steroid production.
Seminiferous tubules (site of spermatogenesis); sertoli cells, spermatogonia (early cell in the production of spermatozoa in the walls of seminiferous tubules).
Interstitial space between the seminiferous tubules; Leydig cells.
Anatomy and Histology-Females
Ovaries: site of reproductive cells and female sex steroid production.
-Granulosa cells
-Thecal cells
-18-22 weeks after conception is when he ovary has its peak number of primordial follicles; these decrease throughout development, remain basically dormant until puberty.
Primordial follicle–>primary follicle (fully grown oocyte)–>secondary follicle (start to get presumptive theca cells)–>early tertiary follicle–>graafian follicle (this forms if follicle goes on to maturation for ovulation-fluid filled sac)
-At any given time, you will have different stages of follicles within the ovary.
Synthesis of progestogens, androgens, and estrogens
-All steroid hormones are synthesized for cholesterol.
-Not all pathways to these hormones are separate pathways that start from cholesterol.
-They can be metabolized in both directions; what may start out as an androgen might end up as an estrogen; progestegin may e metabolized to an androgen or estrogen as well.
The synthesis of progestogens, androgens, and estrogens is closely intertwined; all 3 groups are steroid hormones derived from the metabolism of cholesterol.
-Progestogens activate the Progesterone Receptor; progesterone and a number of therapeutic synthetically altered progesterone derivatives.
-Androgens activate the Androgen Receptors; dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone (DHT), others.
-Estrogens activate the Estrogen Receptors (alpha, beta); 17beta-estradiol (most potent). estrone, and estriol (less potent), others (environmental estrogens).
Progestogens-what do they do?
- Progestogens generally exert anti proliferative effects on the female uterus: endometrium.
- Promote endometrial lining secretion rather than proliferation; promote the switch from proliferation to secretion.
- Progestogens are required for the maintenance of pregnancy.
Synthesis of Progestogens
Cholesterol –> Pregnenolone –> PROGESTERONE
Androgens-what do they do?
-Have masculinizing properties
-Testosterone is considered the classic circulating androgen; can be found in both men and women.
-DHT is the classic intracellular androgen; has a much higher affinity for the receptor (about 10x higher, although testosterone will bind to the receptor); produced at the target organ rather than circulating.
-Androgens required for conversion to a male phenotype during development.
-Required for male sexual maturation (development of sperm, sexual potency, male sexual function).
-Required for male reproductive functions.
Synthesis of Androgens:
Pregnenolone and Progesterone can be metabolized into androgen receptor ligands or androgens (DHEA, testosterone).
Testosterone
The major form of androgen in circulation.
Must be converted into dihydrotestosterone (DHT) in peripheral target tissues; done by 5-alpha-reductase.
-There are 3 different subtypes of 5-alpha-reductase (1, 2, and 3); they are expressed differently in different tissues
Action at the receptor:
-Testosterone can bind the androgen receptor.
-It has only modest affinity and modest androgenic activity.
-Converted in target tissues to the more active dihydrotestosterone (DHT); no DHT could lead to a problem in the male gonads.
MUTATIONS IN 5ALPHA-REDUCTASE-2 LEADS TO PSEUDOVAGINAL PERINEOSCROTAL HYPOSPADIUS!!! No drugs to reverse this; hard to surgicallyrepair because there is not enough of either tissue.
Estrogens-what do they do?
-Share a common feminizing activity; although they are expressed in both males and females.
-Estrogens are derived from the aromatization of precursor androgens.
The enzyme aromatse (Cyp19)
Ovary and placenta are most active.
Adipsoe tissue, hypothalamic neurons, and muscle synthesize aromatase; if you have more fat, you have more arrogates and more circulating estrogen.
Adipose tissue is the main source of estrogen in postmenopausal women and in aging men.
-Exogenous estrogens from food can be ingested and activate estrogenic pathways within the body.
Synthesis of Estrogens:
Start with cholesterol, then get DHEA which is an androgen; aromatase metabolizing androgenic precursors to estrone, estradiol and estriol.
-Aromatase can metabolize testosterone to estradiol; DHT can also be converted by another steroid enzyme to 3beta-A-diol (this is the most potent natural ERbeta ligand); an estrogenic compound that binds to ERbeta
Steroid Hormone Nuclear Receptors
Estrogen Receptor; estradiol Androgen Receptor; testosterone Progesterone Receptor; progesterone Glucocorticoid Receptor; cortisol Mineralocorticoid Receptor; aldosterone -These receptors do have differences, but they are still very much the same; typical structures; makes difficult to target the bidding of just one or the other; cross-talk; differences in where receptors are expressed, can help with what is activated; these receptors do have specific ligands.
Steroid Hormone Action and Metabolism
- Superfamily of nuclear hormone receptors: progestogens, androgens, and estrogens, glucocorticoids, mineralocorticoids, vitamin D, and thyroid hormone.
- Transport- after synthesis, hormones diffuse into the bloodstream; a lot of the mare circulating.
- Bind to carrier proteins: sex-hormone binding globulin (SHBG); high affinity, low levels. AND Albumin; low affinity, high levels.
- Hormone ligands bind to receptor and dimerizes; recruits co-activators/co-repressors.
Progesterone Receptor
- Most progestins have significant cross-reactivity with androgen receptors.
- Prolonged progestin administration produces an androgenic effect.
- Most synthetic progestins used as drugs are modified to minimize their androgenic effects.
Estrogen Receptor
-Two types of estrogen receptors
Classical/genomic: ERalpha/ERbeta
Membrane/non-genomic: GPR30/ERalpha36; activates signaling cascades.
-Many actions of estrogens involve association of the receptor with other transcriptional cofactors.
Specific transcription cofactors are tissue- and ligand- dependent; why we have the SERMs.
Accounts for some of the target specificity.
AR and PR likely share these complexities.
-ER dimerizes, you can either have gene transcription, repression, or selective gene transcription.
HPG Axis: Hypothalamus-Pituitary
IMPORTANT IN DEVELOPMENT, REPRODUCTION, AND SEXUAL DIMORPHISM.
-Secretes gonadotropin-releasing hormone (GnRH)
-GnRH travels via the (hypophyseal) hypothalamic-pituitary portal system.
-Stimulates gonadotroph cells of the anterior pituitary gland.
-Pulsatile secretion of GnRH stimulates gonadotropin (LH,FSH) release from the anterior pituitary.
Continuous application of GnRH suppresses gonadotroph activity of cells in the pituitary gland, can be important in treatment in diseases like prostate cancer.
Important pharmacologic consequences in the administration of exogenous GnRH (chemical castration).
-Postive and negative feedback
-Production of GnRH, FSH, and LH is similar in both males and females; the effects on target tissues are different.
Pituitary target cells in males: Testis
LH
-Stimulates Leydig cells; when LH binds the receptor, inside the Leydig cell, cholesterol is metabolized into prenenolone and then to testosterone, which then diffuses out into the bloodstream or into the sertoli cell.
-The Sertoli cell can either use the testosterone or convert it to estradiol if there is binding of FSH to sertoli cell receptor.
-Increases the synthesis of testosterone
-Testosterone diffuses into neighboring Sertoli cells and the bloodstream.
FSH
-Stimulates Sertoli cells
-Increases the production of androgen binding protein (ABP); maintains high testicular concentrations of testosterone; necessary for spermatogenesis.
-Stimulates the production of other proteins necessary for sperm maturation.
Pituitary target cells in females: Ovaries (pre-ovulation)
FSH
-Stimulates Granulosa cells; stimulates aromatase and can convert androgen precursors to estradiol or other estrogens, which can then diffuse into the circulation.
-Increases production of ESTROGENS.
LH
-Stimulates Theca cells; activates a cascade of genes that allow for metabolism of cholesterol to androgenic precursors that then diffuse over to the granulosa cells.
-Increases production of ANDROGENS
-Androgens diffuse into neighboring Granulosa cells.
LH and FSH have different effects on the ovaries depending on where in the cycle the woman is.
Binding of both LH and FSH in the ovaries is required for production of estradiol.
Pituitary target cells in females: Ovaries (post-ovulation)
- Makes estrogens and progesterone
- In the granulosa cells, you have binding of both LH and FSH.
- Cholesterol is metabolized to progesterone and due to the FSH, estradiol is also produced from aromatase and androgenic precursors.
- LH still binds to the thecal cells.
HPG (Hypothalamic-Pituitary-Gonadal) axis: Feedback in males
-Testosterone produced in Leydig cells acts as a negative regulator of the pituitary gland and the hypothalamus.
-Sertoli cells synthesize and secrete inhibin, books synthesis and secretion of FSH.
-Sertoli cells synthesize and secrete activin: stimulates FSH release and does not affect LH.
Positive and negative feedback depending on how much FSH secretion is needed.
HPG Axis: Feedback in females
-Granulosa production of inhibins and activins; estrogen is more complex than testosterone in men; can involve either positive or negative feedback (depending on follicle stage).
-At ovulation, estrogen can increase the stimulation of FSH and LH.
-It can also inhibit LH, FSH, and GnRH secretion.
-Combination of estradiol and progesterone post-ovulation; synergistically suppresses GnRH, LH, FSH secretion; actions at both the hypothalamus and pituitary gland.
IN MALES, TESTOSTERONE INHIBITED GNRH, LH, AND FSH FOR NEGATIVE FEEDBACK.
IN FEMALES, ESTROGEN CAN DO BOTH NEGATIVE AND POSITIVE FEEDBACK.
Integration of endocrine control: the menstrual cycle
- Cycling of hormones
- Periodicity of 28 days; normal ranges of 24-35 days.
- Onset of puberty until menopause.
Menstrual Cycle Overview
- The portion of the menstrual cycle before ovulation is referred to as either the follicular or proliferative phase.
- Developing ovarian follicle produces most of the gonadal hormones (E2).
- When the follicle is developing, that is when you have the most production of estradiol.
- E2 stimulates cellular proliferation of the endometrium.
- The portion of the menstrual cycle after ovulation is referred to as the luteal or secretory phase.
- Corpus luteum produces progesterone!!
- Progesterone induces the endometrium to become secretory rather than proliferative!!!
Uterus-Proliferative Phase
- Follicles grow
- Estrogens increase
- Leading to proliferation
Ovulation
- Estrogen levels peak at the end of the proliferative phase.
- This peak of estrogen leads to a surge in LH and FSH levels.
- Results in eruption of follicles releasing the oocyte.
- A few hours after ovulation, the remaining follicle (granulosa and theca cells) change to lutein cells; they enlarge and are filled with lipid inclusions, yellow appearance=lutein cells.
Corpus luteum
- Cellular remains of the ruptured ovarian follicle.
- Secretes estrogen and progesterone, not just estrogen.
- Presene of progesterone signals the endometrium to switch from a proliferative to a secretory state.
- Endometrium begins synthesizing proteins for implantation of a fertilized egg.
- Blood supply to the endometrium also increases.
- Secretions from the endometrial glands are very important for the fetus during the first trimester of pregnancy.
- The reason for the switch in these hormones…prepare endometrium for implantation of a fertilized egg.
Uterus: Secretory (luteal) phase
-Corpus luteum produces progesterone and estrogen.
-This leads to decreased proliferation and increased secretion; uterine secretions are important for the embryo.
CORPUS LUTEUM
-If fertilization and implantation does not occur within 14 days…the corpus lute ceases production of estrogen and progesterone and the corpus lute regresses to form corpus albicans; looks like a scar on the ovary, a lot of it is broken down by macrophages.
-Absence of estrogen and progesterone:
Endometrial lining sheds and menstruation begins.
Pituitary inhibition removed, FSH and LH increase; this stimulates estrogen secretion and the development of new ovarian follicles and another cycle.
Uterus: Menstrual Phase: Not proliferating, not secretory, it just sheds its out lining and that is when menstruation starts.
Fertilization and Pregnancy
-Embryo secretes human chorionic gonadotropin (hCG); pregnancy test
-Corpus lute remains viable and secretes PROGESTERONE!!! Rather than regressing into the corpus albicans.
-Production of hCG decreases after 10-12 weeks of pregnancy and the placenta begins to secrete progesterone autonomously; no longer depends on the corpus luteum for progesterone secretion to stay viable.
Even though hCG secretion decreases after 10-12 weeks, it is still detectable in pregnancy tests, it is still more than normal; can detect hCG throughout pregnancy.
Pathophysiology of reproductive tract disorders
- Disruption of the hypothalamic-pituitary-reproduction axis; example: polycystic ovarian syndrome, prolactinoma.
- Common cause of infertility due to disrupted sex hormone production.
- Inappropriate growth of hormone-dependent tissue; examples: breast cancer, prostatic hyperplasia, prostate cancer, endometriosis, endometrial hyperplasia, leiomyomas (uterine fibroids).
- Decreased estrogen or androgen secretion: hypogonadism, menopause.
Polycystic ovarian syndrome (PCOS)
- Characterized by anovulation (failure of the ovary to release ova over a period of time generally exceeding 3 months) and increased levels of plasma androgen.
- Affects between 3-5% of women of reproductive age.
- Diagnosis is typically clinical; concurrent findings of anovulation and hirsutism because of increase in androgens (abnormal growth of hair on a person’s face or body).
- Multiple etiologies are likely to be responsible for PCOS
LH hypothesis of PCOS development
-Observation of increased frequency and amplitude of pituitary LH pulses; 90% of women with PCOS have increased circulating LH; suggests that there is an increase in GnRH activity.
-No accompanied increase in FSH increases only the concentration of androgens, not estrogen!!
-Increased LH activity effects:
Stimulates ovary thecal cells to synthesize increased amounts of androgens: androstenedione and testosterone.
-INCREASED LH AND ANDROGEN LEVELS PREVENT NORMAL FOLLICLE GROWTH!!! This is dependent on estrogen.
Prevents follicle secretion of large amounts of estrogen.
Absence of estrogen “trigger” prevents LH surge and OVULATION.
-Patients with PCOS menstruate irregularly.
Insulin theory of PCOS development
-Observation that many women with PCOS are obese, insulin resistant, and secrete increased insulin.
-Increased insulin:
Decreases the production of sex hormone binding globulin (SHBG); helps transport sex hormones though the bloodstream.
Results in higher concentration of free testosterone; not being carried from metabolism site to their target.
Greater androgenic effects on peripheral tissues.
-Insulin directly synergizes with LH to increase androgen production of theca cells.
