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Reproduction Physiology (Hypothalamus Pituitary Gonad Axis: Male (Male…

- - - - in adult male, GnRH secretion has a continuous (24H) pulsatile pattern
      - in adulte female, follows a cyclic (28 days) pulsatile pattern
    - - During development, hypothalamus is very sensitive to negative feedback of gonadal steroids (testosterone or estrogen)
      - becomes progressively less sensitive as puberty approaches, until the feedback actions characteristic of adults are established by puberty
      - There is also another hypothalamus factor: Kisspeptin, and its reecptor GPR54
      - In absence of either kisspeptin activity or receptor activity, individual (male or female) fails to enter puberty and is infertile
    - - Permanent virilization of hypothalamus which imprints the GnRH secretion pattern as 24H and pulsatile
      - Priming of androgen dependent target issues
    - - FSH initiates spermatogenesis by promoting germ cells to undergo divisions and differentiation within seminiferous tubules of testes
      - FSH works on sertoli cells of seminiferous tubules
        
        These cells surround stem cells and developing sperm, isolating them from the rest of the body (blood testes barrier)
        -prevent an autoimmune response to the haploid sperm cells that could be recognized as foreign bodies
        
        Induce expression of androgen binding protein (ABP) on cell surfaces of sertoli cells.
        
        testosterone-ABP complex provides local supply of testosterone in high conc. near developing sperm which is critical for maturation of sperm
      - Regulation of FSH involves complex balance between stimulation by GnRH from hypothalamus and inhibitory feedback by sex steroids, and by inhibin B from gonads
        -inhibin B secreted by sertoli cells in response to spermatids within the seminiferous tubules
        
        when cohort of mature sperm is released, inhibin B secretion decreases and serum FSH rises -> initiates new cohort of sperm within seminiferous tubule
      - Target cell for LH is leydig cell
        
        secrete testosterone for use as a parcarine within testes and as hormone by peripheral target tissues
  - - - DHT responsible or development and maintenance of male secondary sex characteristics including beard growth, deep voice and growth of prostate
    - - Negatively regulate HPG axis
      - Maintain sperm production
      - development and maintain male genitalia and accessory glands
      - Develop and maintain secondary sex characteristics
      - Increase lean muscle mass
  - - - receptor resistance in which estrogen receptor is inactivated resulting in continual longitudinal growth of skeleton
      - Insufficiency of estrogen in which aromatase gene inactivated resulting in undetectable plasma estrogen levels, but normal plasma testosterone levels
        
        low bone density, continued longitudinal growth of skeleton
        
        Administration of estrogen to these individuals induced epiphyseal closure limiting elongation of skeleton and partial correction of bone density
- - - - Common with males and females
      - Process of producing sperm/ova coordinated by hypothalamus which secretes GnRH (gonadotropin releasing hormone) in a pulsatile manner
      - In turn stimulates anterior pituitary to secrete both FSH and LH
      - In both males and females, androgens (testosterone) produced in the gonad needed for development of ovum or sperm
      - Production of inhibin B by cells decreases FSH secretion while sex hormones like testosterone and estrogen regulate GnRH, LH and FSH secretion
    - - Cyclic pattern of hypothalamic secretion controls menstrual cycle
      - Starting at puberty, hypothalamus secretes GnRH which leads to LH and FSH secretion from anterior pituitary
      - LH acts on theca cells of ovary to secrete androgen (testosterone)
      - FSH acts on follicles in ovary (specifically the granulosa cells that surround the ovum)
        
        contains aromatase which converts local androgen to estrogen
      - -ve feedback:
        
        Estrogen exert -ve feedback blocking secretion of GnRH, LH and FSH
        
        Granulosa cells also secrete inhibin which selectively suppresses FSH secretion
    - - Regulation of GnRH release is through hypothalamic neurons expressing kisspeptin
      - Kisspeptin producing neurons express estrogen receptors a and B as well as androgen receptor (inhibited when bound)
      - When kisspeptin neurons are activated, release kisspeptin which increases production of GnRH by GnRH neurons
      - Other factors affect GnRH secretion, such as leptin and circadian signals, which may also act through kisspeptin signals
        
        Leptin produced by adipose -> decreased leptin levels though to directly or indirectly reduce kisspeptin release to prevent GnRH secretion to allow organism to conserve energy by reducing fertility
    - - Childhood: low levels of GnRH and estrogen -> only follicle maturation is gonadotropin-independent, no ovulation
      - onset of puberty may be due to decreased -ve feedback of estrogen on GnRH, allowing increased GnRH production
      - Resulting increase in estrogen production cause maturation of secondary sex characteristics and icnreased bone growth
      - Role of leptin: more adipose -> start earlier -> earlier menarche
  - - - 2 primary functions
        
        oogenesis
        
        ovum and its urrounding granulosa cells mature into a structure called follicle
        
        Secretion of estrogens and progestins
      - Primary type of estrogen is Beta-estradiol, with small amt of estrone being secreted
        
        estradiol is also the most potent form
      - Estriol is oxidative product produced in liver from estrone and estradiol
      - Both progesterone and testosterone can be converted to estrogens
      - Estrogen develops and maintains female secondary sex characteristics and cause proliferation of endometrium after menstruation
      - Estrogen formed in ovary when theca cells produce testosterone that the granulosa cells convert to estrogen
      - Most prevalent and important progestin is progesterone
        
        one impt role is to induce secretory phase of uterus in preparation for implantation of embryo
    - - Ovarian germ cell population changes in no. over time
        
        peak stem cell population at about 5th month of gestation, followed by rapid fall
        
        No. at birth is around 10-20 million
        
        During prepubertal and reproductive periods, further reduction in oocyte no. such that only 400-500 oocytes actually mature to vulation (called atresia, or death of non-successful follicles)
        
        loss of oocytes is fundamental basis of menopause
    - - growth of ea follicle begins with gonadotropin independent phase
        
        during this phase, primordial follicles converted to follicle with a Zona Pellucida and several layers of granulosa cells
        
        process regulated by growth factors within ovary, occurs throughout infancy, childhood and adulthoot
      - in infancy and childhood, without significant levels of LH and FSH, follicles undergo atresia and do not become fully mature
  - - - Follicular phase
        
        From day 1 to 14
        
        At beginning, many follicles that had begun to develop during gonadotropin-independent phase continue to mature in response to FSH binding to granulosa cells (gonadotropin-dependent phase)
        
        FSH stimulates granulosa cells to produce aromatase, converting androgens produced by theca cells to estrogen
        
        LH stimulates theca cells surrounding the follicle to produce androgens (testosterone)
        
        Estrogen produced further stimulates granulosa cells
        
        estrogen and FSH increase expression of LH and FSH receptors on granulosa cells, estrogen also increase expression of LH receptors on theca cells.
        
        Granulosa cells continue to secrete increasing amounts of estrogen which feed back in a -ve manner to regulate FSH, plasma FSH declines
        
        FSH also regulated by inhibin B secreted by granulosa cells (regulates from the pituitary)
        
        Each month, 6-12 follicles start to mature but only one is chosen to ovulate
        
        this follicle expresses highest no. of FSH and LH receptors and is thus more sensitive to those hormones
        
        survives and others die (atresia) due to falling FSH levels
        
        between 12 -14, rapid rise in estrogen by granulosa cells acts in a positive manner, resulting in increase kisspeptin within hypothalamus, increasing GnRH secretion and consequently a surge in FSH and LH secretion, and about 18 hrs after peak of LH surge, ovulation of chosen ovum occurs
        
        unique to females that express a second site of synapse with cell body of GnRH producing neurons and stimulate release under increased estrogen levels
      - Luteal phase
        
        Days 14-28
        
        In ovary, now empty follicle converts to a progesterone secreting tissue called corpus luteum
        
        The same LH surge that causes ovulation initiates conversion of granulosa cells to become granulosa lutein cells and the theca cells to become theca lutein cells
        
        Corpus luteum secretes both estrogen and progesterone with theca lutein cells producing androgens and granulosa lutein cells converting it to estrogen and progesterone
        
        Progesterone initiate secretory phase of endometrium
        
        In luteal phase, estrogen and inhibin from corpus luteum inhibits FSH and LH secretion from pituitary, as well as GnrRH.
        
        estrogen inhibition of LH and FSH is stronger in the presence of progesterone
        
        If fertilization does not occur, then 12-14 days after ovulation, corpus luteum degenerates by apoptosis and ceases estrogen and progesterone production
        
        Decrease in progesterone allows for menstruation and decrease in estrogen allows for increased GnRH production to begin the cycle again
      - Ovulation
        
        dependent on LH surge which initiates several processes
        
        LH causes oocyte to finish 1st meiotic division and becomes arrested at metaphase II
        
        LH cause granulosa cells to produce progesterone and the progesterone receptor
        
        Newly formed progesterone acts on its receptors of granulosa cells in autocrine manner to cause expression of proteolytic enzyme that weaken the wall of follicle
        
        increase prostaglandin production initiate inflammatory proces,s vasodilation and contraction of cells to help ovum escape follicle
        
        both progesterone and prostaglandin production are necessary for ovulation
        
        Ovulation can be blocked through use of NSAIDS that inhibit prostaglandin synthesis
        
        Egg leaves ovary surrounded by a layer of cumulus cells, with inner cells contacting the egg called corona radiata
    - - Proliferative phase
        
        regulated by estrogen from developing follicle during days 1-14
        
        During this time, estrogen causes uterine wall to thicken and uterine glands to develop
        
        under control of estrogen, cervix produces clear mucous which facilitates movement of sperm into uterus
        
        in contrast to later, during secretory phase when progesterone is abundant, mucous becomes thick to produce a plug that protects the uterus from bacteria from the vagina
      - Secretory phase
        
        regulated by progesterone produced by corpus luteum during days 14-28
        
        Progesterone prepare uterus for possibility of embryo implantation by causing endometrial glands to produce glycogen
        
        Progesterone also decrease no of estrogen receptors which stops the proliferative effects of estrogen
        
        In absence of fertilization and implantation, corpus luteum degenerates and progesterone levels decline late in menstrual cycle
        
        Decreased levels of progesterone and estrogen cause prostaglandins to be produced in endometrium
        
        vascular constriction and enhanced uterine smooth muscle activity
        
        Menses, sloughing off of endometrium, ensues
        
        overproduction of prostaglandins can lead to menstrual cramps due to uterine smooth muscle contraction as well as systemic effects such as vomitting and headaches
        
        Successful implantation and pregnancy require a continuous production of progesterone
        
        newly formed embryo secretes the hormon, human chorionic gonadotrophin (hCG) a few days after fertilization, which stimulates corpus luteum to produce progesterone and estrogen during first trimester -> hCG is homologue of LH
        
        Maintenance of estrogen levels prevents FSH and LH from increasing to start follicular maturation and thus the next cycle
        
        hCG used to access viability of fetus and is basis of pregnancy test
        
        if no successful implantation -> no hCG produced -> corpus luteum degenerates
      - Mechanism of action for estrogen
        
        steroid hormones -> act as transcription factors
        
        In uterus and breast, estrogen up regulates estrogen receptors and primes tissue for progesterone by increasing no of progesterone receptors expressed
        
        Thus, estrogen can amplify its own effects and preps tissues for a sufficient enough response for progesterone
        
        Continual exposure to unopposed estrogen can result in pathological stimulation of target tissues (endometrial and/or breast cancer)
        
        Two different estrogen receptors, alpha and beta, that have different tissue distributions -> different affinities for synthetic estrogens -> need to be considered
        
        In contrast, progesterone-dependent transcription down regulates estrogen receptor, facilitating differentiation instead of proliferation
      - Role of androgen in females
        
        Androgens produced by adrenal cortex and ovaries
        
        Play a role in sex drive, growth of skeletal muscle and pubic and axillary hair
      - Fertilization
        
        Once ovulated, eggs survive for about 24 hours before degenerating, during which egg travels down oviduct towards the uterus
        
        Sperms that have entered the female tract must go through capacitation by contacting the surface of epithelium of isthmus portion of oviduct
        
        During capacitation, cholesterol is lost from sperm plasma membrane to make it more fluid, and is necessary for sperm to be able to bind to ZP and undergo acrosome reaction to penetrate the egg
        
        Capacitation also important for inducing hyperactive state of sperm motility, which is necessary for penetrating layers of the egg
        
        Once sperm comes into contact with egg, usually in ampulla, must penetrate layer of cumulus cells to reach ZP, which then triggers a regulated exocytosis process in the sperm, the acrosome reaction
        
        Fusion of acrosome with sperm plasma membrane releases enzymes that digest ZP and allow sperm access to egg plasma membrane, which then fuces together and the sperm enters the egg (with exception of tail plasma membrane)
        
        Once entered, several process prevent polyspermy
        
        rapid depolarization of egg plasma membrane
        
        cortical reaction where egg is stimulated by an increase in intracellular calcium to release granules that digest ZP and cross link proteins to prevent other sperm from gaining access to egg plasma membrane
        
        Increase in intracellular Ca also cause egg nucleus to finish 2nd meiotic division, and once diploid zygote is formed, contains both male centrosomes and female mitochondria
      - Pregnancy
        
        if fertilization and implantation are successful, syncitiotrophoblast of embryo will produce hCG which acts on corpus luteum to prevent it from degenerating and to stimulate estrogen and progesterone ssecretion
        
        hCG levels icrease and peak at 10-12 weeks of pregnancy
        
        once hCG levels decrease, 3 months into pregnancy, corpus luteum regress, but production of progesterone and estrogen is taken over by the placenta (continues to increase)
        
        In order to make estrogen, placenta must convert androgens received from tissues such as fetal adrenal glands
      - Lactation
        
        Starting in puberty, estrogen levels increase, secretion of prolactin increases
        
        During puberty, estrogen stimulates mammary gland duct branching and growth while progesterone and prolactin stimulate alveolar growth
        
        Only very high levels of prolactin stimulate production of milk
        
        Mammary gland does not become fully developed until prolactin (from maternal pituitary) and estrogen, progesterone and placental lactogen (from placenta) act on mammary gland during pregnancy
        
        During pregnancy when estrogen is very high, stimulation of milk production by prolactin is inhibited until delivery when source of estrogen, the placenta, is delivered
        
        After several months of breast feeding, due to decreased levels of estrogen, basal levels of prolactin decrease, but during each episode of nursing, prolactin levels are high to induce milk production
        
        during nursing, suckling of baby causes oxytocin to be released from the pituitary, causing contraction of myoepithelial cells of mammary gland and ejection of milk
        
        Suckling of baby can also prevent ovulation, possibly through effects on kisspeptin neurons
        
        can prevent pregnancy for years
        
        due to inhibitory effects of estrogen on prolactin release, nursing mothers often prescribed progesterone only birth control pills
        
        Feedback inhibition of Lactation (FIL)
        
        prevent damage to breast from being to full
        
        autocrine peptide hormone that inhibits further milk production until volume depleted during consumption
        
        Control vol. of milk
      - Menopause
        
        At around age 50, a woman stops having menstrual cycles and reach menopause, which occurs due to lack of viable follicles
        
        Without follicles to mature and product estrogen and inhibin, lack of -ve feedback on hypothalamus and pituitary, resulting in high FSH and LH levels in peri and postmenopausal women
        
        Post menopausal women do produce some estrogen due to conversion of adrenal androgens by aromatase, but levels are low enough that estrogen dependent tissues such as breasts and genitalia atrophy
        
        Bone protecting effects of estrogen are lost -> osteoporosis
        
        Loss of effects of estrogens on vasculature cause hot flashes, when arterioles of the skin dilate and there is a feelinf of warmth and sweating
        
        Protective effects of estrogen on CVS are lost as well
      - Oral contraceptives
        
        Usually a combination of synthetic estrogen and progesterone
        
        Doses are lower than what would be normally found in body due to prolonged half life by slowing metabolism of it in the liver
        
        act by inhibiting pituitary secretion of LH through -ve feedback, often preventing ovulation
        
        Some pills such as progesterone only pills are not as effective in preventing ovulation, but they prevent pregnancy by affecting cervical mucus which prevents sperm from entering uterus or by making endometrium unable to facilitate implantation
        
        Periodic withdrawal of steroid is needed to allow for sloughing of uterine flow (withdrawal bleeding)
- - - - Zygote:
        Cell resulting from ovum + sperm
      - Blastomeres:
        daughter cells of zygote
      - Morula:
        Solid ball of about 16 blastomeres (3 days in oviduct)
      - Blastocyst:
        After morula develops a fluid filled cavity (implants in endometrium)
      - Embryo:
        embryonic disc, to 7 weeks of fetal age, major structures present
      - Fetus:
        after embryo to birth
      - Conceptus:
        all tissues that develop from zygote
    - - Hemochorioendothelial placenta in humans
        
        maternal blood bathes syncitiotrophoblast, but separated by chorion-placenta endothelial lining (keeps maternal blood separate from fetal)
      - 2 cellular components
        
        Cytotrophblast
        
        Invade endometrium like a malignancy, progenitors of syncitiotrophoblast
        
        Syncitiotrophoblast
        
        True syncitium with no cell borders, covered with microvili
      - Villous
        
        Finger of placental tissue consisting of outer layer of syncitiotrophoblast, inner layer of cytotrophoblast and a fetal blood vessel
      - Cotyledon
        
        lobe of placenta supplied by mainstream villous that branches, about 10-30 make up the average placenta
      - Chorion laeve
        
        trophoblast toward uterine cavity degenerate and become stuck to amniotic membrane, these two layers become the fetal membranes
        
        stuck to decidua with fetal fibronectin
      - Intervillous space
        
        amorphous space between fingerlike villi into which maternal blood flows via spiral arteries, blood squirts toward fetal surface and dissipates laterally
      - Plcaental transport
        
        Simple diffusion:
        O2, CO2, water and electrolytes
        
        Facilitated/selective diffusion:
        
        Glucose, Vit C, irone, amino acids, trace elements
        
        active transport:
        Calcium
        
        Endocytosis:
        IgG
    - - Vol increase 500-1000 times, weight increase 16x, receive 10% of increased cardiac output at term, mildly detrorotated due to colon resting behind it on the left
      - Decidua
        
        highly modified endometrium of pregnancy, supports early blastocyst, limit placental invasion, shed after pregnancy
      - Spiral arteries
        
        becom utero-placental vessels that feed intervillous space, in pregnancy, transformed into just a shell characterized by absence of smooth muscle or endothelial cells, draining veins transformed into large uterine sinuses
      - Myometrium
        
        Bundles of smooth muscle united by CT, increases tremendously during pregnancy via hypertrophy
      - gap junctions
        
        intercellular channels between myometrial cells that increase throughout pregnancy and especially just before labor
      - Oxytocin
        
        peptide produced by posterior pituitary that increase uterine contractions, receptors increase dramatically during pregnancy
    - - Pituitary enlarges
      - Abdominal striae (stretch marks)
      - Hyperpigmentation - chloasma, melasma, linea nigra
        
        increased MSH due to estrogen (?)
      - Spider angiomata
      - Lordosis to maintain balance with enlarging uterus
  - - - Human Chorionic Gonadotropin (hCG)
        
        Produced by syncitiotrophoblast
        
        alpha subunit identical to LH, HFSH TSH
        
        beta subunit unique to hCG
        
        levels peak around weeks 10-14 then fall off
      - Human placental lactogen
        
        similar in structure to human growth hormone
        
        Produced by syncitiotrophoblast, production icreases throughout gestation, up to 1 g/day in late pregnancy
        
        Believed to be fetal nutrient supply in times of starvation
        
        Lipolytic, increase maternal free fatty acid levels, and has anti-insulin action insuring steady supply of glucose for fetus
      - Chorionic adrenocorticotrophin
        
        ACTH like, function unknown
      - Chorionic thyrotropin
        
        Unknown
      - Relaxin
        
        made by corpus luteum, decidua and placenta
        
        Promotes myometrial relaxation, but role is unknown
    - - Estrogens (C18)
        
        daily amt of estrogen produced by near term placenta is 1000x ovulatory woman
        
        Increases throughout pregnancy, then abruptly drops after delivery
        
        Placenta cannot make estrogens from cholesterol as it is missing steroid 17 alpha hydroxylase/ 17,20 desmolase
        
        cant convert C to C19 steroids needed for estrogen synthesis
        
        Fetal adrenal gland produces dehydroepiandrosterone sulfate (DHEA-S), an estrogen precursor that is converted to estradiol (E2) and estriol (E3) C18 steroids in placenta
        
        During pregnancy
        
        increases Vit K dependent clotting factors production in liver
        
        VII, VIII, IX, X, fibrinogen increases, free protein S decresaes, hypercoagulable state
        
        binding globulins produced in liver increase like Thyroid binding globulins (TBG)
        
        Increases myometrial intracellular ATP - more excitable
        
        affects breast DUCTAL development (more like proliferation)
      - Progesterone (C21)
        
        Produced by placenta, progressively increases throughout pregnancy
        
        decrease smooth muscle/myometrial excitability
        
        Induce regractoriness to Angiotensin II
        
        Induce breast alveolar development (proliferation)
        
        Increases central respiratory drive - lowers CO2 threshold at respiratory center
  - - - heart rate increases gradually up to 10-15 BPM
      - Stroke vol increases through mid pregnancy, then declines towards term
      - Cardiac output (CO = HR x SV) increases 30-50% through pregnancy, plateauing in 3rd trimester
        
        there is a big jump (10-50%) in labor and immediately postpartum
        
        physiological systolic ejection murmur occurs due to increased flow
      - Systemic vascular resistance falls until 24 weeks then returns to normal at term
        
        due to progesterone (loss of AII responsiveness recovered near term), Nitric Oxide and placenta serving as a big AV fistula
      - Blood pressure declines through midtrimester and returns to normal at term -related to SVR
    - - Total lung capacity slightly reduced even though diaphragm rises 4cm and transverse thoracic diameter increases
      - Respiratory rate
        
        not changed
      - Tidal volume
        
        increased 40%
      - Minute Volume
        
        MV = RR x TV
        
        Increased, leading to "hyperventilation" during pregnancy, thus respiratory alkalosis, PaCO2 falls, due to progesterone
      - Oxygen consumption
        
        increased
      - PaO2
        
        unchanged due to bigger increase in minute volume than consumption
      - Functional residual capacity
        
        decreased slightly due to slight fall in total lung capacity and increase TV
    - - Plasma volume increase 40-45%, fall in oncotic pressure
      - Total red cell vol increase 20-30%, erythroid hyperplasia, increased reticulocyte count, increased erythropoietin
      - Total blood volume increases 33%
      - Hematocrit falls due to dilution effect
      - White Blood Cell count
        
        increase due to an increase in neutrophiles, other WBC unchanged though cell mediated immunity is depressed (cytotoxic T cells decrease)
      - Platelet Count
        
        May drift down slightly, but remain above 150K
      - Fibrinogen increased
      - Clotting factors
        
        increased Vit K dependent factors, clotting time stays the same as does Prothrombin time
    - - anatomy
        
        increase in renal size
        
        Physiologic hydronephrosis and hydroureter due to progesterone and uterine compression ( calices and ureters become dilated)
        
        Bladder capacity reduced
        
        Hyperemia of trigone, makes emptying difficult
      - Glomerular filtration rate (GFR)
        
        Due to renal plasma flow increase, increaes too by 50%
      - Creatinine clearance goes up, serum creatinine and BUN goes down
      - Glucosuria
        
        in 1/6 of pregnant women, due to increased GFR, reabsorptive capabilities not able to match amount of glucose in urine, thus glucosuria
      - Urinary Tract Infections
        
        Increased due to poor bladder emptying with residual urine an dincreased vesicoureteral reflux
        
        5-10% get UTI and will get pyelonephritis if untreated
      - Bicarbonate
        
        lower due to compensatory metabolic acidosis for respiratory alkalosis
    - - gastric emptying time delayed
      - Lower esophageal sphincter tone
        
        decreased, increased risk of aspiration (lead to vomitting)
      - Constipation/ hemorrhoids increased
      - Liver
        
        increased protein synthesis, no anatomic changes so AST/ALT unchanged, Alkaline phosphatase elevated due to placenta
      - Serum total protein, serum albumin
        
        decreased due to dilutional effect of plasma volume, decreased oncotic presure
      - Cholesterol and fatty acids
        
        Increased due to hPL effect (human placental lactogen)
    - - Thyroid
        
        increase TBG and total hormone, but free T3 and T4 stays the same
        
        TSH levels decreased
        
        more markedly at the start due to hCG being similar to TSH
      - fasting glucose
        
        drops due to facilitated transport towards fetus out of maternal circulation
        
        post prandial glucose increased due to increased insulin resistance
        
        Serum insulin levels increased as there is islet cell hypertrophy and icnreased relsease of insulin to overcome resistance
      - Accelerated starvation
        
        switch of maternal fuels from glucose to lipids to insure steady supply of glucose for fetus
      - Adrenal
        
        increased cortisol and aldosterone
    - - Weight gain (25-35 pounds)
      - Calories (average 300kcals/day, increase protein to 60g from 45gm
      - Iron
        
        Depleted stores in reproductive age women, recommended 30mg elemental ifron supplementation for all pregnant women
      - Folic acid
        
        to decrease neural tube defects
      - Calcium 1g/day
      - Pica
        
        eating (craving) nonfood substances
      - Strict vegans
        
        may run out of B12, Ca also due to no dairy products