Chapter 1 A Perspective on Human Genetics

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1 Chapter 15 Hormone and Female Reproductive Physiology Nam Deuk Kim, Ph.D.

2 1. Anatomy of Female Reproductive System Organs Female reproductive tract Oviducts (uterine or Fallopian tubes) In close association with ovaries Pick up ova on ovulation Serve as site for fertilization Uterus Responsible for maintenance of fetus during development Responsible for expelling fetus at end of pregnancy Vagina Muscular, expandable tube that connects uterus to external environment Lower portion is cervix» Cervical canal» Single, small opening that serves as pathway for sperm» Serves as passageway for delivery of baby from uterus

3 Vagina Vaginal opening» Located in perineal region between urethral opening and anal opening» Partially covered by thin mucous membrane, hymen (typically disrupted by first sexual intercourse) Labia minora and labia majora» Skin folds that surround vaginal and urethral openings Clitoris Vulva» Small erotic structure located at anterior end of folds of labia minora Collective term for female external genitalia

4 Female Reproductive System

6 Fig Reproductive organs of the human female.

7 Functions Production of ova (oogenesis) Reception of sperm Transport of sperm and ovum to common site for union (fertilization or conception) Product of fertilization is known as an embryo After first two months of intrauterine development, embryo is known as a fetus Maintenance of the developing fetus until it can survive in outside world (gestation or pregnancy) Formation of placenta (exchange organ between mother and fetus) Giving birth to the baby (parturition) Nourishing infant after birth by milk production (lactation)

8 The major physiological activities of the ovary are hormonogenesis and gametogenesis More complex than male reproductive physiology Characterized by complex cycling Ovaries Primary female reproductive organs Produce ova (oogenesis) Secrete female sex hormones Estrogen» Essential for ova maturation and release» Establishment of female secondary sexual characteristics» Essential for transport of sperm from vagina to fertilization site in oviduct» Contributes to breast development in anticipation of lactation Progesterone» Important in preparing suitable environment for nourishing a developing embryo/fetus» Contributes to breasts ability to produce milk

9 Oogenesis Identical steps of chromosome replication and division during gamete production in both sexes Timing and end result are very different Spermatogenesis Accomplished within two months Postpubertal male can produce several hundred million sperm each day Each primary spermatocyte yields four equally viable spermatozoa Oogenesis Take anywhere from 12 to 50 years to complete on cyclic basis from onset of puberty until menopause Female born with limited, largely nonrenewable supply of germ cells Each primary oocyte yields only one cytoplasm-rich ovum and three cytoplasm-poor polar bodies that disintegrate

10 Oogonia Oogenesis Undifferentiated primordial germ cells in fetal ovaries Divide mitotically to give rise to 6 million to 7 million oogonia by fifth month of gestation During last part of fetal life begin early steps of first meiotic division but do not complete it Now known as primary oocytes Contain diploid number of 46 replicated chromosomes Remain in meiotic arrest for years until they are prepared for ovulation At birth only about 1 million primary follicles About 250,000 primary follicles (oocytes) by puberty About 400 will mature and release ova; 99.98% never ovulate but instead undergo atresia.

11 Primary oocyte Oogenesis Surrounded by single layer of granulosa cells Oocyte + granulosa cells primary follicle Primary follicle After development starts there are two possible fates Reach maturity and ovulate Degenerate to form scar tissue (atresia) Between puberty and menopause Follicles develop into secondary (antral) follicles on cyclic basis

12 Just before ovulation Oogenesis Primary oocyte completes its first meiotic division yielding First polar body Secondary oocyte Ovulated Sperm entry triggers second meiotic division which produces» Secondary polar body (haploid)» Mature haploid ovum which unites with haploid sperm cell during fertilization

13 Oogenesis Fig Ovarian follicles may be found in four basic conditions: at rest, growing, atretic, or ready to ovulate.

14 Oogenesis

15 Ovarian Cycle Average ovarian cycle lasts 28 days Normally interrupted only by pregnancy Finally terminated by menopause Consists of two alternating phases Follicular phase Dominated by presence of maturing follicles Luteal phase Characterized by presence of corpus luteum

16 Follicular phase Operates first half of cycle Ovarian Cycle Granulosa cells of some primary follicles proliferate Oocyte inside each follicle enlarges Theca cells in follicle secrete increased amounts of estrogen Rapid follicular growth continues during follicular phase One follicle usually grows more rapidly and matured about 14 days after onset of follicular development Follicle ruptures to release oocyte from ovary Event is called ovulation Released oocyte enters oviduct where it may or may not be fertilized

17 Ovarian Cycle Luteal phase Last 14 days of ovarian cycle Old follicular cells undergo structural transformation to form corpus luteum Becomes highly vascularized Becomes fully functional within four days after ovulation Continues to increase in size for another four or five days If released ovum is not fertilized and does not implant, corpus luteum degenerates within about 14 days after its formation

18 Development of the Follicle, Ovulation, and Formation and Degeneration of the Corpus Luteum

19 Fig The primate ovarian follicular cycle.

20 Antrum Thecal cells Ovum (primary oocyte) Granulosa cells Fig SEM of the human Graafian follicle.

21 컴퓨터그래픽으로그린배란장면

22 2. Ovarian Steroid Hormones Production of estrogen by an ovarian follicle

23 Estrogen biosynthesis requires androgen production in thecal cells and aromatization in granulosa cells. Progesterone biosynthesis occurs primarily in luteal cells. Fig Two-cell, twogonadotropin hypothesis of estrogen synthesis.

24 Fig Biosynthesis and metabolism of estradiol.

25 Paracrine-acting growth factors regulate ovarian function. - IGF-I: regulating the ovarian cycle, folliculogenesis, and granulosa cell steroidogenesis - IGF-1: affect FSH-induced enhancement of progesterone, estrogen, and camp production, as well as LH receptor induction. Fig Role of IGFs in ovarian steroidogenesis.

26 3. Physiological Roles of Ovarian Steroid Hormones

4. Mechanisms of Action of Ovarian Steroid Hormones Estrogen receptors trigger gene activation Estrogen receptor isoforms (ERα, ERβ) mediate genomic actions of estrogen.

27 4. Mechanisms of Action of Ovarian Steroid Hormones Estrogen receptors trigger gene activation Estrogen receptor isoforms (ERα, ERβ) mediate genomic actions of estrogen. ERs initially localized to either cytoplasm or nucleoplasm. Estrogen response element (ERE). Progesterone s genomic actions are mediated by progesterone receptors A and B (PR A, PR B ).

28 Estrogen-Induced Changes in Cell Behavior Estrogen-Induced Stimulation of Cell Proliferation

29 5. Neuroendocrine Control of Ovarian Function Complex hormonal interactions During follicular phase, rise in FSH signals ovarian follicle to secrete more estrogen Rise in estrogen feeds back to inhibit FHS secretion which declines as follicular phase proceeds LH rises in follicular phase As it peaks in mid-cycle, it triggers ovulation Estrogen output decreases and mature follicle is converted to a corpus luteum Corpus luteum secretes progesterone and estrogen during luteal phase Progesterone output inhibits release of FSH and LH Low LH corpus luteum degenerates Progesterone levels decline FSH can start to rise again, initiating new cycle

Intrafollicular polypeptides regulate folliculogenesis and oocyte maturation. Inhibins: gonadal polypeptide; inhibitory to pituitary FSH secretion.

30 Intrafollicular polypeptides regulate folliculogenesis and oocyte maturation. Inhibins: gonadal polypeptide; inhibitory to pituitary FSH secretion. Activins: can enhance basal secretion of FSH in a dose-dependent manner in vitro w/o affecting the secretion of LH. Feedback control of FSH and tonic LH secretion during the follicular phase.

31 Fig Structural relationships between inhibins and activins.

32 6. Mammalian Reproductive Cycles: Ovarian Cycle

33 Fig Cycle of uterine endometrial growth and development during nonfertile and fertile cycles in the human female.

35 Control of the LH surge at ovulation

36 Feedback control during the luteal phase

Why Caffeine Can Reduce Fertility in Women ( 연합뉴스 2011.5.27) 미국네바다대학의과대학의숀워드 (Sean M. Ward) 박사는커피의주성분인카페인이난소로부터난자가자궁으로이동하는것을방해함.

37 Why Caffeine Can Reduce Fertility in Women ( 연합뉴스 ) 미국네바다대학의과대학의숀워드 (Sean M. Ward) 박사는커피의주성분인카페인이난소로부터난자가자궁으로이동하는것을방해함. 커피를하루 4 잔이상마시면임신가능성이 25% 줄어든다는것을포함, 지나친카페인섭취가여성의생식기능에부정적영향을미친다는여러연구결과가발표되었으나정확한이유는지금까지밝혀진적이없음. 워드박사는카페인이난자를자궁으로운반하는데필요한나팔관의수축을억제한다는사실이쥐실험결과밝혀졌다고말했음. 카페인은난자를자궁으로내려보내기위해진행되는나팔관수축의파동을조절하는나팔관벽속의특수세포인박동조율세포 (pacemaker cell) 의활동을방해함. 난자가어떻게나팔관을통해자궁으로이동하는지에대해서는자세하게밝혀진것이없다. 나팔관내막에있는털처럼생긴섬모 (cilia) 가움직이면서난자를자궁으로밀어내는것으로알려졌을뿐임. 그러나워드박사는난자를자궁으로이동시키는데는섬모보다는나팔관의수축이더큰역할을한다고밝혔음. 이결과는커피나음료를통해카페인을많이섭취하는여성은임신하는데시간이오래걸리는이유를설명해주는것임. 이연구결과는또수정란이자궁으로이동하지못하고나팔관에머물러자라는위험한현상인자궁외임신의원인을이해하는데도도움이될것이라고워드박사는덧붙였음 (Inhibitory effect of caffeine on pacemaker activity in the oviduct is mediated by camp-regulated conductances. Dixon et al., 163(4), , British Journal of Pharmacology)

38 남성불임의원인과극복방법 정자생성의문제 : 남성불임의원인은정자의생성에문제가있는경우가가장많다. 불임의원인중전체의 80~90% 를차지한다. 남성이여성에게정상적인임신을시키기위해서는정액 1cc 당 4,000 만마리의정자가있어야하고, 그중 50% 는정상적인모양이고운동성이활발해야가능하다. 그런데정자가아예생성되지않는무정자증이거나, 정자가생성되더라도수가적고운동성이약하거나, 정자수가많더라도모양이기형인경우가훨씬많다면임신의가능성이떨어지게된다. - 정자형성이되지않는이유는대개정자가생성되는고환에문제가있기때문. 대표적인것이정계정맥류로주로 90% 이상이왼쪽에서발생한다. 외관상으로는특별한증상이없지만통증과함께고환의위축이일어나는일이종종있다. - 정계정맥류는사춘기때주로발생하는데, 전체남성의 8~13% 에서발견될정도로흔한질병이기도하다. 정계정맥류가불임을일으키는원인은고환의온도상승때문으로추정한다. 사우나를자주하는남성이나몸에꼭맞는속옷을입는남성들은고환의온도가높아질수있으므로주의하는것이좋다. 정자이동의문제 : 정자를만들어내는기능에는이상이없지만, 정자의이동통로가막혀있다면임신이되지않는다. 전체불임부부의 7% 정도가정로 ( 精路 ) 폐색으로인해임신이되지않고있다. 정로에심한외상을입거나결핵, 임질등의질환에의해부고환에염증이생기면서기능저하가일어나폐색이된경우, 그리고정관수술로인한경우를들수있다. 이렇게되면결과적으로무정자증을불러일으킨다. 사정의문제 : 전혀사정이되지않는무 ( 無 ) 사정과사정은이루어지지만요도밖으로정액이사출되지않고거꾸로방광내로역 ( 逆 ) 사정되는경우에도불임이된다. 섹스후나자위행위직후소변검사시정자가많이섞여있는경우가이에해당된다. 또사정이쉽게일어나지않는지루증의경우에도불임의가능성이높다. 이외에도특발성불임증이라고해서원인을알수없는이유에의해정액의질이저하되어불임이될수있다.

39 여성불임의원인과극복방법 배란의문제 : 전체불임여성의 25% 에서발견된다. 난소에서난자를배출하는것을배란이라고하는데, 예정생리첫날로부터약 2 주전에이루어진다. 뇌하수체호르몬중의하나인유즙분비호르몬의양이증가한경우나, 갑상선이나당뇨같은대사장애및결핵, 간질환등의내과적인질환등이있을때는배란을방해하게되어월경이있어도무배란이되거나무월경을초래하기도한다. 나팔관의문제 : 전체불임여성의 25% 가해당된다. 배란이잘이루어진다고해도정자와난자가만나수정이이루어지고수정된난자가착상을하기위해자궁을향해이동을하는통로인나팔관에이상이있으면불임이된다. 그중나팔관폐쇄가가장대표적이다. 나팔관이막히게되는원인으로는임신중절, 자연유산, 성병및여성내부생식기의염증성질환등이있다. 자궁질환의경우 : 자궁은수정란이착상해태아를키워내는장소이다. 그런데이곳에염증이나자궁근종, 암등이있거나선천적인자궁불량이나기형상태라면착상이제대로되지않아불임이되거나, 착상이되었다해도임신을유지하기가힘들어자연유산이나조산이되는원인이된다.

40 7. Pathophysiology 1) Amenorrhea: the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation (breastfeeding), the latter also forming the basis of a form of contraception known as the lactational amenorrhea method. Outside of the reproductive years there is absence of menses during childhood and after menopause. Amenorrhoea is a symptom with many potential causes. Primary amenorrhea (menstruation cycles never starting) may be caused by developmental problems such as the congenital absence of the uterus, or failure of the ovary to receive or maintain egg cells. Also, delay in pubertal development will lead to primary amenorrhoea. It is defined as an absence of secondary sexual characteristics by age 14 with no menarche or normal secondary sexual characteristics but no menarche by 16 years of age.

41 Secondary amenorrhea (menstruation cycles ceasing) is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, from premature menopause or intrauterine scar formation. It is defined as the absence of menses for three months in a woman with previously normal menstruation or nine months for women with a history of oligomenorrhea. 2) Altered gonadotropin secretion in female athletes: Secondary amenorrhea Weight loss and decreased body fat-to-lean ratios Reversible with weight gain 3) Isolated gonadotropin deficiency: Bihormonal deficiency of FSH and LH. Administration of GnRH enhances FSH and LH secretion.

42 4) Dysmenorrhea A. Primary Pelvic organs are normal Most common type Pain is crampy, caused by protaglandins Begins just prior to menstruation Lasts for one or two days after onset of menstrual flow Menstrual periods are painless for the first two years after menarche because the cycles are anovulatory (no ovulation) Dysmenorrhea occurs when ovulatory cycles begin B. Secondary Result of various diseases of the pelvic organs, such as endometriosis Treatment Aspirin Other anti-inflammatory drugs Oral contraceptive pills

43 5) Polycysts and Tumors of the Ovary They are benign Ovarian cysts Arise from ovarian follicles or corpora lutea Are common Not large Regress spontaneously Endometrial cysts Endometrial deposits in ovary filled with old blood and debris Section of normal ovary

teeth, bone, parts of gastrointestinal tract, thyroid, and

44 Benign cystic teratoma (dermoid cyst) Arise from unfertilized ova that undergo neoplastic change Often contain skin, hair, teeth, bone, parts of gastrointestinal tract, thyroid, and other tissues growing in a jumbled fashion Malignant teratoma Very rare

45 Ovarian Tumors Cystadenoma Cystadenocarcinoma Fibroma Granulosa-theca cell tumor Male hormone-producing tumors

46 Benign Cystic Ovarian Tumors

It refers to a male pattern of body hair (androgenic hair) and it is therefore primarily of cosmetic and psychological concern.

47 6) Hirsutism Hirsutism or frazonism: the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair (androgenic hair) and it is therefore primarily of cosmetic and psychological concern. Hirsutism is a symptom rather than a disease and may be a sign of a more serious medical condition, especially if it develops well after puberty. The amount and location of the hair is measured by a Ferriman-Gallwey score.

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대한한의학원전학회지26권4호-교정본(1125).hwp http://www.wonjeon.org http://dx.doi.org/10.14369/skmc.2013.26.4.267 熱入血室證에 대한 小考 1 2 慶熙大學校大學校韓醫學科大學原典學敎室韓醫學古典硏究所白裕相1, 2 *117) A Study on the Pattern of 'Heat Entering The Blood Chamber' 1, Baik 1