Endocrinology Topics
HPG Axis and Puberty
The hypothalamus - pituitary - gonadal axis (HPG) is controlled by the interaction between the gonadotropins FSH and LH and gonadal hormones. The gonadotropins are glycoprotein heterodimeric proteins made in the gonadotrope cells of the anterior pituitary. They form dimers with the aGSU protein. In females, lutenizing hormone (LH, lutropin) induces ovulation, initiates steroidogenesis in the ovarian follicle, and maintains secretory function of the corpus luteum. In males, LH stimulates Leydig cells to produce testosterone. LH has a half-life of about 60 minutes.
In
females, follicle-stimulating hormone (FSH, follitropin) stimulates development
of ovarian follicles and secretion of estrogen. In males FSH stimulates spermatogenesis
and sex-hormone binding globulin (?). The half life of FSH is about 170 minutes.
Both LH and FSH signal through cAMP pathways. The gonadal hormones estrogen
(mostly in females), testosterone (mostly in males) and inhibin (both males
and females) signal to the hypothalamus and gonadothropes to dicrease LH and
FSH release.
During puberty, there is an increase in excitatory and decrease in inhibitory CNS inputs to the hypothalamus axis that lead to incresed activity of the GnRH releasing neurons. LH relese increases occur during sleep.
Puberty is the time when body changes particular to the sex occur and when reproduction becomes possible. Gonadarche, maturation of the HPG axis, occurs at the beguining of puberty (?). At gonadarche, ovaries begin to secrete estrogens, and testes and adrenals secrete androgens. Adrenarche refers to the adrenal androgen relelease that occurs between 7 and 14 years of age. Adrenarche drives pubic and axilary hair growth (pubarche) in both girls and boys.
During puberty, the external genitalia develops adult characteristics: labia and clitoris grows in girls while in boys the scrotum, testes and penis mature. There is also linear bone growth and the body contours form acording to phenotypic sex. Closure of the epiphyses occurs earlier in girls than in boys, maybe driven by estrogen in both. Girls develop breasts (thelarche) and have their first menstruation, while boys are able to ejaculate and develop a deeper voice. Boys may also suffer excess acne (due to androgens?).
Estrogen is responsible for stimulating growth of the uterus, determination of the female figure by controlling fat deposition, closure of the epiphyses, and effects on personality and sexual behviour.
The order in which pubertal and peripubertal changes occur may vary between individuals. In general, increased gonadotropins stimulate ovaries to produce estrogens and the increased estrogen levels promote development of secondary female sex characteristics: breast development beguins, bone maturation, fat distribution, etc. Since estrogen levels vary during puiberty, girls may get follicular development but failed ovulation. Still the uterine endometrium proliferates and regresses eventually leading to the first menstruation.
The CNS/pituitary system of girls matures in response to estrogen positive feedback. Acquisition of preovulatory competence allows estrogen to prime the LH surge that induces ovulation (?).
When pubertal changes occur before age 8 in girls or age 10 in boys they are precocius. True Precocious Puberty is the early but normal sequence of pubertal developmental events often of unknown causes. True Precocious puberty may be due to brain disease, for example a tumor that secretes GnRH. Central precocious puberty (?) may be caused by CNS lesions and/ore hypothalamic deffects.
Pseudo Precocious Puberty is due to periopheral hypersecretion of estrogens or androgens or by ingestion of steroids. Peripheral steroid hypersecretion may originate in the adrenals, ovary, or testis. Congenital Adrenal Hyperplasia, ovarian cysts, testotoxicosis (familial), or tumors may of any steroid-producing tissue will lead to high steroid levels. Chorionic gonadfotropin-secreting tumors and hypothyroidism (mechanism unknown) are also causes of Pseudo Precocious Puberty. The most common form of precocious puberty, Premature Thelarche, is mostly benign.
Delayed puberty is treated with GnRH.
Take Quiz: [Q1] [Q2] [Q3]
Back to Basics: Topic 1
Topic 2
Advance Topics: Topic 1
Topic 2
Female Reproductive Endocrinology
Oogenesis beguins in the fetal ovary. Primary oocytes are formed when oogonia enter prophase of meiosis 1 at weeks 11-12 and then arrest. They then become surrounded by granulosa cells and the complete structure is known as the primary follicle. By weeks 20-28 there are about 7 million primary follicles, but some start degenerating to leave only about 2 million by birth and 300,000 by puberty.
Ovarian
follicle development refers to the intermitent maturation of germ cells in the
female. One germ cells reaches maturity about every 28 days. This process beguins
at puberty and lasts only for a limited time. The primary follicle develops
into a secondary follicle: with a liquid-filled antrum and membrana granulosa.
The secondary follicle develops into a Graafian follicle, which is no able to
release the ovum. After ovulation, the follicle becoms a corpus luteum: a round,
steroidogenic cellular mass.
The ovarian follicle serves several key functions:
Not
all primary follicles will develop and lead to ovulation. Some follicles nomally
become atretic, i.e. degenerate, either from the resting state or after developing
into Graafian follicles. When more than one follicles develop at about the same
time, the first in-phase (?) follicle will block the LH receptor of competing
follicles with an inhibitory peptide to prevent further action by LH to produce
ovulation.
The cyclical production of oocytes is associated with changes in ovarian hormone production and important changes to other parts of the female reproductive system. Estrogen and progesterone re produced by the ovaries. Steroid production in the ovary is explained by the two cell theory. Membrana granulosa cells (outher membrane of the follicle) are separated from the surrounding theca by a distinct basement membrane. The theca interna consists of androgen-synthesizing cells and capillaries; external to these are fibroblast-like cells of the theca externa. LH stimulates the theca interna cells (via cAMP) to synthesize testosterone and androstenedione. These either pass into local capillaries or cross the basement membrane into the adjacent membrana granulosa cells. The membrana granulosa cells are stimulated by FSH to produce estrogens by the aromatization of the testosterone and androstenedione. The estrogens then enter the circulation or pass into the antrum of the follicle and act on the oocyte.
Estrogen signals through estrogen receptors (ERs). There are two types: ER alpha and ER beta. The beta form was more recently discovered by Gustavson laboratory (Karolinska, Sweden). The ERs are nuclear receptors that may act as hetero or homodimer on estrogen response elements (EREs) in similar fashion to GR (form heat shock complexes, etc.). They are present in many species (rat, mouse, human) and different tissues have different expression patterns:
Estradiol has lesser affinity for ERb than ERa but some environmental estrogens have more afinity for ERb than ERa. ERb is found in breast and bone and this may have implications for the treatment of breast cancer and osteoporosis. Many companies are designing drugs to prevent osteoporosis in post-menopausal women without adverse effects on breast or uterine cancer rates. Tamoxifen may be just an antagonist for beta (both an agonist and antagonist for alpha).
Estrogen Receptor alpha knockout (Lubahn et al., PNAS 90: 11162; 1993) was expected to be a lethal phenotype since estrogen is important in development, but that is not the case in mice. Mice initially appear normal, there is a normal sex ratio, but the animals are infertile (oth sexes). There is no functional corpora lutea in females and sperm count is low in males. Breast development is poor (model for breast cancer research?), and bone density is low (model for osteoporosis research?).
Only one human "knockout" case has been reported (Smith et al., NEJM 331:1056; 1994), a young male patient with a truncated ER alpha (no DNA binding nor ligand binding domains). The patient is very tall, with young bone age, and low bone density. It is not yet known if he is infertile.
ER-beta knockout mice (Krege et al. Proc Natl Acad Sci U S A 1998;95:15677) exhibit phenotypes distinct from ER-alpha knockout mice. They developed normally. Females are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild type mice. Superovulation experiments indicated that this reduction in fertility is a result of reduced ovarian efficiency. Mutant females had normal breast development and lactated normally. Young mutant male mice showed no overt abnormalities and reproduced normally. Older mutant males displayed signs of prostate and bladder hyperplasia. These results indicate that ERb is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation.
In mice lacking both ER alpha and ER beta (Couse, Korach et al. Science 1999;286:2328-31), both sexes exhibit normal reproductive tract development but are infertile. Ovaries of adult abERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Mullerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.
The
effects of estrogen on mammary cancer are studied by a rodent model that follows
the effects of ovariectomy on 7,12-dimethylbenzanthracene (DMBA) induced mammary
tumors. DMBA is a genotoxic carcinogen, metabolized in the body to a DNA mutagen
(not estrogen-like). Whn one dose of DMBA is given at about 55 days old (puberty),
the rats get tumors in about 2 months. Estrogen dependent tumors have high ER
levels (>normal). Estrogen independent tumors have low or absent ER levels
Progesterone signals through
the progesterone nuclear receptor protein (PR), which acts in similar fashion
to GR and ER. The corpus luteum is major source of circulating progesterone.
PRKO males are fertile, females infertile (Chappell et al. Endocrinology 1997
Oct;138 (10):4147-4152). PRKO embryos develop to adulthood at a normal Mendelian
frequency with no deviation in the sex ratio, but there is impairment in the
induction of a sexual behavioral response and extensive reproductive abnormalities
in female: lack of ovulation, uterine hyperplasia and inflammation, and severely
limited mammary gland development (Lydon,
1996; J. Steroid Biochem. Mol. Biol. 56, 67-77).
Take Quiz: [Q1] [Q2] [Q3]
Back to Basics: Topic 1
Topic 2
Advance Topics: Topic 1
Topic 2
Female Reproductive Cycle
The female reproductive cycle in primates is known as the menstrual cycle. The first half of the cycle, just before ovulation, is known as the follicular phase. Estrogen production predominates during the follicular phase and is responsible for proliferation of the endometrium, conditions in vagina that are conductive to sperm survival (low pH, watery mucus), and maturation of the vaginal epithelium. At the cellular level, estrogen increases the synthesis of progesterone receptors therefore progesterone response is dependent on estrogenization. Estrogen also provides both negative and positive feedback to the hypothalamus and pituitary. At their peak levels, estrogens induces a surge of LH secretion by the anterior pituitary, which signals to the follicle for ovulation. Ovulation prediction kits measure LH levels.
The second half of the cycle, just after ovulation, is known as the luteal phase. Progesterone production predominates during the luteal phase and provides negative feedback to the hypothalamus and pituitary. Progesterone causes and increase in body temperature, production of secretory endometrium and secretion of thick cervical mucus with leukocytes, making they uterus ready for implantation, and promotes conditions in the vagina that are not conductive to sperm survival (high pH, thicker mucus). It also stimulates synthesis of 17-hydroxysteroid dehydrogenase, which deactivates estradiol in target tissues by converting it to the less potent estrone.
If there is no implantation, the corpus luteum regreses (about day 12), leading to a sharp drop in progesterone levels towards the end of the cycle. Since progesterone is not avaiable to maintain the thick endometrium, the endometrial wall degenerates and flows out into the vagina as menstruation.
In most non-primate mamals, the female reproductive cycle may not involve the monthly uterine maturation/sloughing and includes a period of highten receptivity to mating known as the estrus cycle (adjective "estrous"; from the greek "mad desire" or "heat"). Many species are spontaneous ovulators, and ovulation occurs at a given time of the cycle. Others like the cat and the rabbit may be induced ovulators, which procede to ovulate after mating. In some species, the female reproductive cycle is associated with the seasons and/or fertilized eggs reside in the uterine cavity for a while before implantating (delayed implantation) allowing flexibility between mating and birth. In most species reproductive success depends on environmental conditions such as light availability and pherormones.
The
definitions of contraception and abortion may overlap depending on the branch
of science. In Biology, contraception is usually considered the prevention of
fertilization, while in Medicine is the prevention of implantation.
Oral contraceptives for women are preparations of estrogens and progestogens either in combination or as sequential treatments or both. They provide combined negative feedback to hypothalamus and pituitary, preventing the LH/FSH surge and follicular phase rise in FSH. Therefore women using oral contraceptives do not experience ovarian follicular development. Endogenous estradiol is kept low as LH and FSH are suppressed. A sequential regime simulates the normal sequence of events more closely. The contraceptive effect of oral preparations is threefold: there is no ovulation, cervical secretions are thicker and that may block travel of sperm, and the uterine lining is altered so implantation is less likely.
Progesterone-only contraceptives include Depo-Provera and NorPlant, and have the same threefold effect as combination oral contraceptives. Depo-Provera consists of a progestogen injection every 3 months. NorPlant progestogen silastic capsules (6) are implanted under skin and the contraceptive effect lasts up to 5 yrs.
Emergency contraception (ECP, aka Morning after pill or “plan B” pills) usually consists of high dose of both estrogen and progesterone that prevent implantation.
Pregnancy termination may be done by surgical or pharmacological early pregnancy interruption/abortion. RU 486 (aka mifipristone) is a progesterone antagonist with high affinity for the PR and may make heat shock proteins bind tighter to the PR (rather than cause their release). RU 486 is 96-99% effective
There are risks and benefits associated with use of oral contraceptives. There is a slight increase in breast cancer risk with a ratio about 1.3 that decreases to 1.0 after 10 years. There is a large reduction in endometrial cancer to a 0.5 risk ratio when oral contraceptives are used and this effect may last up to 20 years after discontinuing the pills. Ovarian cancer is the most lethal of the female reproductive malignancies. Oral contraceptives, however, significantly reduce the incidence by 40% and it may be as much as 80% in women who have used the pill 10 years or longer. Cervical cancer is present more often in contraceptive pill users than nonusers. This results in an increased risk ratio of about 1.5-1.9. An uncommon form of cervical cancer, adenocarcinoma, also shows an increased risk ratio of about 2.0-2.5 with pill use.
Ovulation
ceases at menopause due to a failure of the ovary to respond to gonadotropins.
The onset of menopause is associated with a drop in number of follicles for
growth, and a fertility declinesfrom about 10 years prior to menopause (perimenopause).
There is no relationship between onset of menarche, number of children or time
of first child and onset of menopause. The nutritional status may affect onset
of menopause, thus averaging 49.8 yrs in North America, 51.4 yrs in the Netherlands,
44 yrs in Punjab (India) and <44 yrs in New Guinea. The overall? median age
at menopause is about 50 yrs (earlier in smokers). Genetics may affect the onset
of menopause. One
hundred years ago women rarely lived beyond menopause
Climacterium is the period before the end of reproductive period (?). Perimenopause (premenopause or menopausal transition) is still a loosely defined, may be about 10 years of symptoms prior to last menses. Establishing the timing of perimenopause is hard, unlike menopause which strictly is the time point 12 months after final menses. Perimenopause roughly starts at 47.5 yrs and lasts a median of 4 yrs.
The main changes associated with perimenopause are ovarian mass decrease (after about age 35) and are less responsive to gonadotropins, and high FSH levels, but dramatic fluctuations may be more characteristic of this time. Symptoms include changes in menstrual pattern/nature, hot flashes, night sweats, sleep disturbances, PMS symptoms, and sexual difficulties. Treatments to ease the symptoms of perimenopause include lifestyle changes (diet, minerals, exercise), low-dose oral contraceptives, low-dose transdermal estrogen, herbal remedies and antidepressants. Since fertility drops during perimenopause, artificial insemination/surgical implantation of fertilized ovum may be required in order to concive.
Changes after menopuse is reached include drier skin, osteoporosis, some breast atrophy, and vaginal mucosa dries/atrophies. Some women get menopausal flushes/flashes associated with LH surges (not caused by them) similar to a withdrawal syndrome. Since they have an underlying adrenergic mechanism, alpha adrenergic agonists can help. Libido may decrease, although this is controversial and hard to assess.
Estrogen production drops off dramatically after menopause, and this reduction is associated with vascular and bone disease. Cholesterol goes up about 6% and the risk of heart disease increases 3 times after menopause. Heart disease is the major cause of death in women after age 45, while accidents are major cause of death in women before age 45. Major bone mass loss occur in the 3-6 years after menopause.
Hormone Replacement Therapy (HRT) is used to decrease the incidence of heart disease and osteoporosis in postmenopausal woman. HRT may be estrogen alone (e.g. Premarin), or estrogen plus progesterone (e.g. Prempro). Progesterone lowers risk of uterine cancers.
HRT is controversial because some breast cancer depend on sex steroids for proliferation (25-30% are hormone-dependent). If ER levels in breast tumors are high the cancer may be hormone-dependent. Early onset of menarche correlates with breast cancer incidence, but the disease incidence is lower in athletes. Smoking is an added risk factor not only in breast/endometrial cancer but also heart disease and osteoporosis.
Tamoxifen (Nolvadex, Zeneca Group PLC, U.K.) and Raloxifen (Evista, Eli Lilly) are selective estrogen receptor modulators (SERMs) that act like estrogen in certain tissues but not others. Tamoxifen may reduce some risk of breast cancer in some women predisposed to getting the disease (FDA September 1998) by blocking estrogen from binding ER in cancer cells, but risks include blood clots, higher risk of uterine cancer, hot flashes, and vaginal dryness. Raloxiphen prevents osteoporosis and lowers cholesterol levels, although not as well as estrogen replacement, but there is no increased incidence of breast or uterine cancer observed to date. Raloxifen side effects may include hot flashes and leg cramps.
Phytoestyrogens are plant-derived estrogenic compounds (e.g. some isoflavones such as genistein) rich in legumes such as red clover and also available as dietary supplements (e.g. Promensil). They can act as estrogens or anti-estrogens. There may be a correlation between low levels of some cancers in Asian countries with diets rich in soy products.
Take Quiz: [Q1] [Q2] [Q3]
Back to Basics: Topic 1
Topic 2
Advance Topics: Topic 1
Topic 2
Pregnancy
At about day 6 after ovulation/fertilization, the zygote implants into the endometrial epithelium of the uterus. After implantation, the endometrium undergoes decidualization, i.e. formation of the deidua or implantation chamber with three main layers: decidua basalis, decidua parietalis and decidua capsularis.
The zygote develops into a morula, then a blastocyst. The blastocyst has two parts: the embryo per se (embryoblast) and a connection to the mother (tropoblast). Tropoblast cells proliferate to form invasive syncytiotrophoblast that establishes connections to maternal capillaries. Gonadal steroids may be required for implantation (blastocyst may generate or accumulate steroids) and there may be high levels of ER and PR at implantation sites. The syncytiotrophoblast also secretes chorionic gobadotropin (hCG) which prevents regression of the corpus luteum (i.e. takes over from LH) and stimulates progesterone biosynthesis by luteal cells to maintain the pregnancy (until the placenta takes over).
hCG
is a glycoprotein heterodimeric hormone of the same family as TSH, FSH and LH.
The bhGC protein dimerizes with aGSU to form hGC hormone. The hCG receptors
may be the same LH receptors, which activate cAMP signaling (the beta subunits
of hCG and LH are very similar). In mammals other than rabbits, rats and primates,
prolactin also maintains corpus luteum function.
hCG is the basis of modern pregnancy tests. Normal hCG levels are about 5 mIU/ml or less but by 10 weeks after fertilization increases to about 100,000 mIU/ml. Pregnancy tests may measure whole hCG or just hCG beta subunit. Hospital tests (blood) range from 2 to 10 mIU/ml and are quantitative (e.g. emergency room diagnosis of pregnancy). Home tests (urine; OTC, over the counter) measure hCG ranges from 25 to 50 mIU/ml and usually give a yes/no answer. OTC tests are set high so that do not detect until later in pregnancy since many pregnancies spontaneously abort early (therefore positive result more likely to lead to continued pregnancy). Home test kits are also available for farm animals.
hCG pregnancy tests are usually monoclonal antibody based (ie. recognize one specific "determinant" - important as hCG beta subunit has strong homology to LH beta subunit - want to avoid cross-reaction). Most assays are immunocolorimetric sandwich assays using two anti-hCG antibodies: the first antibody used "captures" the hCG protein, then after washing a second antibody is used for detection. Such assays would use colorimetric detection (latex particles, dye-filled liposomes, etc) or enzymes (e.g. alkaline phosphatase) that catalyzes color change and compare the results to an hCG positive control.
Modern methods must be easy and accurate and hi-tech therefore cannot inject an African clawed toad with patient's urine and look for spawning. The phrase, "The rabbit died," came to be a euphemism for a positive pregnancy test in the late 1920s and early 1930s. Around 1927 it was discovered that if you injected the urine of a pregnant woman (therefore containing hCG) into a rabbit, there would be corpora hemorrhagica in the ovaries of the rabbit. These bulging masses on the ovaries could not be seen without killing the rabbit to inspect the ovaries, so invariably, every rabbit died, even if the woman wasn't pregnant. In later years, they were able to do surgery on the rabbit, examining its ovaries without killing it. So the test could be done on a live rabbit, whether the woman was pregnant or not.
Placental lactrogen (aka chorionic somatomammotropin, hCS or hPL) is a member of the "growth hormones" superfamily of proteins like GH and prolactin. hPL is made in the syncytiotrophoblast epithelial cells of the chorionic villi of the placenta of many mammals and serves to augment maternal functions. Production starts at about th 6th week of pregnancy and achieves peak levels during mid- and late pregnancy, reaching levels 3 times higher than maternal GH. The primary role of hPL may be to stimulate mammary gland development without causing milk secretion. Prolactin can then promote m8ilk secretion after partuition. hPL may alter maternal metabolism to ensure adequate glucose, amino acids and minerals for the fetus, countering maternal insulin. It may also directly promote fetal growth.
During
Pregnancy, estrogen causes growth of the breast duct system and myometrial hypertrophy
together with floiud retention and increase in uterine blood flow. Progesterone
inhibits cotractions and reduces snooth muscle tone, rises body temperature,
increases growth of breast alveoli, limits prepartum actions of prolactin on
lactogenesis and decreases sensitivity to oxytocin.
Progesterone binds to the oxytocin receptor (OT-R) with an affinity of 20 nM. This is less than its affinity for the PR (< 1nM) but still compatible with the very high progesterone concentration that is normal during pregnancy (500 nM). Grazzini et al (1998. Nature 392, 509-512) showed that, in rat, progesterone linked to a membrane-impermeable molecule still blocks the OT-R, that progesterone binding reduces the number of OT-R available to bind oxytocin, and that the calcium mobilization alowed by oxytocin was inhibited by progesterone in less than a minute. While progesterone does not inhibit the human OTR, its derivative 5b-dihydroprogesterone does. Other non-genomic effects of progesterone include induction of oocyte maturation.
During the first 2 months of pregnancy, estrogens and progesterones are produced by the corpus luteum (supported by hCG from the sycyntiotrophoblast). After 2 months the feto-placental unit itself produces enough steroids to support the pregancy. The placenta produces pregnenolone from cholesterol that can be converted to progesterone. Pregnenolone from the placenta is also converted to the estradiol precursors 17a-hydroxypregnenolone and DHEA (in their sulfated forms) by the fetal adrenal cortex. The precursors from the fetus are then converted to estradiol by the placenta.
Parturition is timed to begin only after the developing embryo is sufficiently mature to survive outside the womb. It has been postulated that the signal for the initiation of parturition arises from the fetus although the nature and source of this signal remain obscure. Hippocrates suggested that the signal for paturition is when the placenta can no longer keep up with the nutritional needs of the fetus. Barcroft did experiments in the 1930's with seep and suggested that late-term fetus require more oxygen than the placenta can supply. But it is not understood how the fetus senses oxygen levels nor the mechanism to beguin the labor process. It seems that the status of the fetal brain is important. Babies with anecephaly (anterior parts of brain malformed or missing) are born dead and very late. Sheep that eat the herb Veratrum califonicum (Western False Hellabore, California Corn Lily) give birth very late to deformed lambs with pituitary and hypothalamus defects. Experiments in sheep by Mont Liggins showed that removal of the pituitary or adrenals at gestation day 115 made the lambs been born much after the normal 150 days. On the other hand, ACTH or cortisol given at day 120 made the lambs be born early (4 days after treatment for ACTH, 3 days for cortisol). Fetal cortisol is important in sheep: it promotes conversion of progesterone to estrogens in the placenta. In mice, a surfactant protein secreted by the maturing fetal lung acts as a hormone that signals the initiation of partuition.
The role of cortisol is primate parturition is not known. In fetal monkeys the signal may be DHEA-SO4 from the adrenals converted to estrogens in placenta. In primates estrogen and progesteron levels drop markedly at birth (due to unknown causes) and seem to lead to both increased uterine oxytocine receptors and prolactin release. The demise of the corpus luteum and prolacting release may also play a role in the timing of parturition. Regardless of the exact mechanism, once the number of available oxytocin receptors increase, oxytocin can induce labor by both increasing uterine motility and prostaglanding synthesis (prostaglandings also increase uterine motility). Promotion of cortisol release from the fetal adrenal cortex by prolactin may also play a role.
Relaxin is a hormone made by the corpus luteum and decidua, chemically related to insulin. Its levels start increasing at mid-term and drop suddenly near birth (at least in rats). Relaxin has diverse actions during pregnancy: relaxes uterine muscle and the pubic bone ligament, promotes of growth and dilation of the cervix, growth and quiescence of the uterus, growth and development of the mammary gland and nipple, and regulation of cardiovascular function. Relaxin stimulates cAMP production target cells and Hsu, et al. (2002; Science 295 pp 671-674) demonstrate that two orphan G protein-coupled receptors, LGR7 and LGR8, are capable of mediating the action of relaxin through a cAMP-dependent pathway.
Mammary gland development at puberty is regulated by estrogens, progesterone and glucocorticoids ( and growth hormone ?). The adult mammary gland is prepared and maintaied for lactation by prolactin (lactogenesis, breast development), placental lactrogen (hPL) and glucocorticoids. Prolactin secretion may be regulated by the rising estrogen levels before birth. In pregnant females, lactotropes hypertrophy and proliferate, and there may be recruitment of somatotropes (common developmental origin) to act as lactotrpes. Suckling triggers oxytocin release, which in turn facilitates milk ejection. The lactating female has low plasma estrogens and high prolactin, and ovolation stops (lactational amenorrhea). At weaning, prolactin levels drops, while LH and estrogen rise.
Take Quiz: [Q1] [Q2] [Q3]
Back to Basics: Topic 1
Topic 2
Advance Topics: Topic 1
Topic 2
Male
Reproductive Endocrinology
Testosterone and its active metabolites DHT and estradiol are the main hormones resposible for the male phenotype. Testosterone and DHT act through the androgen receptor (AR), a nuclear receptor like ER, PR, GR, etc.
5-10 mg testosterone are made daily in Leydig (interstitial) cells of the testis. Androgen binding globulin (androgen binding protein, ABP) binds testosterone and DHT in Sertoli cells and tubules. Testosterone binding globulin (TeBG) binds testosterone in plasma (2% free, 44% TeBG, 54% albumin).
Testosterone is deactivated by metabolism to epiandrosterone, etiocholanolone, and androsterone in liver, then excreted in urine.
LH (and prolactin?) stimulates testosterone production by the Leydig cells. Testosterone and FSH act on Sertoli cells to stimulate spermatogenesis. Sertoli cells also produce MIS, activin and inhibin. Testosterone and inhibin feed back to the hypothalamus/pituitary to decrease LH and FSH secretion. Activin stimulates LH and FSH secretion (?).
Spermatogenesis is really a two step process: seminal fluid formation (in the male) and capacitation (in the female). Sperm mature as they pass through the epididymis (12 days) becoming more motile, aquiring chromatin alterations, tail modification, and loosing the cytoplasm. The epididymis also stores sperm. While in the epidimis, fluid from seminal vesicles is added (60% final vol), which contains contains fructose and prostaglandins, and fluid from the prostate is added (20% final vol), which contains spermine and zinc.
Capacitation takes place in the fallopian tubes of the female. Spermatazoa need time in the female before they can fertilize optimally (2-6 hours). At this time there is increased flagellar beat rate and faster movement, and the acrosome reaction occurs, which allows sperm to fuse with ovum.
Male rats were castrated and given low dose testosterone implants (lower levels than normal). The rats still behaved nomally, copulating with ovarectomized females given estradiol supplementation (receptive), but not with ovarectomized females wirhout estradiol supplementation (not receptive). Spinal cord neurons are active during copulation and shrink without testosterone. Examination of the male rats after copulating (or just sharing cage with unreceptive female) showed the all had the same number of neuron but that the neuron were smaller in copulators. This suggests that differences in behavior can induce differences in brain/CNS anatomy (Nature 389, 801; 1997).
Paul Bernhardt et al (University of Utah) have discovered a physiological effect on the male spectators who root for successful teams which may help explain the fanatical attraction to sports. Men who cheer for winning sports teams experience the same kind of testosterone surges as the athletes themselves. Levels of the tstosterone fell in fans of the losing team. Surges of testosterone could account for post-game celebrations that sometimes get out of hand. Competition between male marine mammals also seem to boost testosterone leves and thus increase sexual potency and fertility.
Androstenedione is a steroid commonly (and usually illegaly) used by athlets . Too much androgen shuts off the body's own production of testosterone. This can impair normal testicular function and MIGHT stunt growth in children and adolescents. Recent data points to a greater conversion of androstenedione to biologically active estrogens rather than androgens. To date, no studies have shown that Andro can increase muscle size or strength, but with high doses it might do so.
The main methods of male contraception are condoms and vasectomy. Vasectomy is the surgical interruption of the vas deferens. Spermatogenesis continues but the sperm is resorbed or stored. Ejaculation is normal, but there is no sperm in semen. There are no hormonal changes resulting from vasectomy, although antisperm antibodies form.
There has been poor success in search for a male hormonal/pharmacological contraceptive. It is easier to stop 1 ovum per month in females than to stop millions sperm in males. Also, key event of the sper life, sperm migration, capacitation, fertilization & implantation, occur in the women. Some possibilities for a male contraceptive include:
Turner et al (J Clin Endocrinol Metab. 2003 Oct;88(10):4659) performed a contraceptive efficacy study of 55 healthy men in stable fertile relationships. Testosterone (four 200-mg implants, every 4 or 6 months) and 300 mg depot medroxyprogesterone acetate, im, every 3 months were administered. No pregnancies occurred in 426 person-months. Sperm density fell rapidly, so 94% of men entered the efficacy phase by 3 months, with only 2 of 55 (3.6%) men not sufficiently suppressed to enter efficacy. A few men treated with testosterone implants at 6-month intervals demonstrated androgen deficiency symptoms but there were no serious adverse effects related to drug exposure.
Rex
A. Hess et al. (1997. Nature 390: 509) showed that estrogen regulates the reabsorption
of luminal fluid in the head of the epididymis. In the ERKO males, sperm enter
the epididymis diluted (rather than concentrated), resulting in infertility.
The ERKO male is infertile, testes are normal until puberty, when they begin
to degenerate. Sperm is abnormal and diluted. The efferent ductules of the ERKO
mice were dilated, and the epithelium was smaller and had less cilia. It seems
that back presure due to excess fluid leads to testicular atrophy. Ligature
experiments of the efferent ductule were done to to assess fluid retention and
compared wild type to ERKO. Luminal area decreased by 80% in wild type and by
14% in wild type treated with antiestrogen (ICI). But in ERKO mice luminal area
increased by 45%. Therefore the anti-estrogen only partially simulated the ERKO
mouse, maybe because estrogen effects are complex, or maybe because the ICI
has opposite effects on ER beta. Human ERKO males have (??!!) poor sperm viability.
Tamoxifen (mixed estrogen agonist/antagonist) is used to increase sperm counts
in men. This paper is important to our understanding of estrogen roles in males
and may also provide clues to the role of environmental estrogens in the reported
declines of sperm counts in human males and in males of other species such as
alligators (??).
Take Quiz: [Q1] [Q2] [Q3]
Back to Basics: Topic 1
Topic 2
Advance Topics: Topic 1
Topic 2
Activins and Inhibins
Activins and inhibins were discovered as gonadal peptides that either inhibited (inhibin) or activated (activin) pituitary follicle stimulating hormone (FSH) production. FSH regulates sperm maturation in the Sertoli cells of the testes and regulates follicle maturation in the granulosa cells of the ovary. Inhibin isolated from gonadal fluid suppressed secretion of FSH from anterior pituitary cells. Activin was found during inhibin purification as an HPLC fraction that stimulated, rather than suppressed, pituitary FSH production (Vale et al. Nature 321: p776. (1986) - activin A; Ling et al. Nature 321: p779. (1986) - activin AB). Inhibin is produced by the testes and the ovaries, but also also in brain, pituitary, adrenal, spleen, placenta, bone marrow, kidney. Activin is produced by the germ cells of the testes, ovaries, brain, pituitary gland and erythropoietic tissues.
They are members of the TGFb family of growth and differentiation factors (>> 30 members), whic contains three sub-groups:
Activin and inhibin are dimers of ~120 aa peptides joined by disulfide bonds, combinations of bA, bB and a:
| Activins | Inhibin |
| bA/bA (activin A) | bA/a (inhibin A) |
| bA/bB (activin AB) | bB/a (inhibin B) |
| bB/bB (activin B) | |
| bC (based isoforms in humans) | |
| bD (based forms in frogs) |
Secreted, mature, bioactive peptides are cleaved from the C-terminus of precursors.
In mammalian cell cultures, activin regulates hormone production in placental cells, induces differentiation of erythroblasts and osteoblasts, promotes survival of P19 neural cells (neurotrophic), inhibits proliferation of gonadal cell, endothelial cells, lung epithelial cells and hepatocytes. More roles uncovered frequently:
| Action | Site of action | Effect of inhibin | Effect of activin |
| Basal FSH levels | Pituitary | Inhibits | Activates |
| GnRH promotes FSH release | Pituitary | Inhibits | Activates |
| GRF promotes GH release | Pituitary | Activates | Inhibits |
| Basal ACTH levels | Pituitary | Inhibits | |
| LH promotes androgen | Gonad | Activates | Inhibits |
| FSH promotes estrogen | Gonad | Inhibits | Activates |
| hCG promotes progesterone | Placenta | Inhibits | Activates |
| Erythropoiesis | Bone | Inhibits | Activates |
| Oxytocin release | Brain | Activates |
Activin receptors belong
to the same family of receptors as TGFbs, BMPs, MIS, etc. They are transmembrane
serine/threonine kinases with Type I and Type II subfamilies. Type II receptors
bind ligand on their own. Type I receptors need Type II receptors to bind ligand.
Both receptor types are needed for activin signalling. The activin Type I receptors
are ActR-I, ActR-IB, and TSR-I . The Type II receptors: ActR-II and ActR-IIB.
Ssome receptors may be shared with other TGFb family members
e.g. BMP-7 can interact with ActR-I and ActR-II as well as BMPR-I and BMPR-II
. This leads to a complex combinatorial ligand/receptor possibilities: e.g.
Drosophila punt /Atr-II can bind activin in concert with Atr-I; Drosophila punt
/Atr-II can bind Dpp in concert with thick veins and saxophone. (??)
Follistatin and alpha 2-macroglobulin are two of several activin/inhibin binding proteins. Both are produced in hormonally-regulated fashion by gonads. Follistatin is a glycosylated monomeric protein with higher affinity for activin than inhibin. It suppresses pituitary FSH release, probably by regulating of activin bioavailability.
Alpha 2-macroglobulin is a high mol wt tetrameric protein and a broad spectrum protease inhibitor (?). It binds many cytokines and growth factors, but its role is unclear, maybe regulation of proteolysis or peptide delivery.
<Activin in Xenopus laevis>
In some species, activin acts as a morphogen, a substances deemed to induce morphogenesis or differentiation in target cells. Morphogens themselves are the products of the inductor cells. Morphogenesis is the developmental processes that lead to the characteristic size and shape of the tissue or organs that make up an organism. In chickens, activin induces axial structures (including notochord and somites) in chick blastula hypoblasts.
Activin is produced by vegetal cells and can induce other cells to form mesoderm. Green and Smith had shown that activin activated mesodermal genes in dissociated Xenopus blastula cells in concentration-dependent manner. J.B. Gurdon et al. (Nature 371: p 487 1994) used combinations of Xenopus embryo tissues to demonstrate that the selection of genes expressed by a cell is determined by its distance from a source of activin. Activin served as a long-range signal and spread over at least 10 cell diameters in hours. This works by passive diffusion, by-passing cells that do not themselves respond to the signal or synthesize protein.
Take Quiz: [Q1] [Q2] [Q3]
Back to Basics: Topic 1
Topic 2
Advance Topics: Topic 1
Topic 2
Continue
to "nest topic" or take a test: [T1] [T2] [T3].
Need more practice? Answer the following review questions:
Questions not yet available