Transcript Glucocorticoids (GC)

Steroid-based Drugs
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• Adrenocortical
Hormones
Adrenocortical Hormones
Adrenal gland:
• Medulla:
– produces Epinephrine
(stimulated by sympathetic impulse)
• Cortex:
– Zona glomerulosa – produces Aldosterone
(stimulated by Angiotensin II and ACTH)
– Zona fasciculata – produces Glucocorticoids
(stimulated by ACTH = Corticotropin)
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– Zona reticularis – produces Androgens
(physiological role unclear)
Adrenocortical Hormones
Steroid hormone synthesis:
•
Pregnenolone synthesis is rate-limiting step
•
C21 hydroxylase:
– Prevents hydroxylation of C17 (-> c)
=> Only mineralocorticoids
•
C17 hydroxylase:
– Hydroxylation of C17 (-> f, g) can be followed
by hydroxylation of C11 and C21 (-> h, j, k)
=> Sex hormones and glucocorticoids
•
P450C17a hydroxylase:
– Produces 17-Keto-steroids (-> l)
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=> Sex hormones
Adrenocortical Hormones
Steroid hormone classification:
•
Progesterone:
–
–
–
•
Mineralocorticoids:
–
–
–
•
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C21
C21, C17: -OH
C 3: =O
C11: -OH or =O
Estrogens :
–
–
–
•
C21
C21: -OH
C3: =O
Glucocorticoids :
–
–
–
–
•
C21
C 3: =O
C17: -OH or =O
C18
C17: -OH or =O
C 3: -OH
Androgens :
–
–
–
C19
C17: -OH
C 3: =O
Adrenocortical Hormones
Glucocorticoids (GC):
•
抑制所有型態的發炎反應
•
促進胎兒肺部發育（Promote fetal development (lungs) ）
•
抑制 NFkB nuclear translocation => transcription of proinflammatory
mediators is prevented
•
Lipocortin 向上調節 => 抑制 PLA2 => 不會有 PG 以及 LT 之合成
• 增加的GC 所帶來的不良效應:
–
–
–
–
–
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免疫被壓抑（）Immune suppression
葡萄糖釋放增加 (=>亦即有名的類固醇型糖尿病 “steroid diabetes”)
葡萄糖將會轉變為脂肪=>造成肥胖 adiposity
對於蛋白質的異化增加 => 肌肉萎縮muscle atrophy
鹽分以及水的滯留Salt and water retention (增加的 GC 將會導致 ACTH 降低 =>
因此降低了醛固酮（aldosterone）的數量) => 高血壓（hypertension）
– 骨質疏鬆（Osteoporosis）
NF-κB 整理
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• NF-κB (nuclear factor kappa-light-chain-enhancer of
activated B cells) 本身係一種蛋白質複合體；該複合體扮演轉錄
因子（transcription factor）。可以在所有的細胞中找到 NF-κB
，該蛋白功用牽涉到對於外界壓力之反應、
• 其項目包括（cytokines, free radicals, ultraviolet irradiation,
oxidized LDL以及細菌與病毒抗原之反應） 。
• NF-κB 在對於感染過程中扮演關鍵性角色；倘若NF-κB出了問題
則可能與癌症、發炎、自體免疫相關之。
• 此外 NF-κB 已被證明擁有 synaptic plasticity 以及 memory
NF-κB action 之作用機轉
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Mechanism of NF-κB action. In this figure, the NF-κB heterodimer between Rel
and p50 proteins is used as an example. While in an inactivated state, NF-κB is
located in the cytosol complexed with the inhibitory protein IκBα. Through the
intermediacy of integral membrane receptors, a variety of extracellular signals
can activate the enzyme IκB kinase (IKK). IKK, in turn, phosphorylates the IκBα
protein, which results in ubiquitination, dissociation of IκBα from NF-κB, and
eventual degradation of IκBα by the proteosome. The activated NF-κB is then
translocated into the nucleus where it binds to specific sequences of DNA called
response elements (RE). The DNA/NF-κB complex then recruits other proteins
such a coactivators and RNA polymerase, which transcribe downstream DNA
into mRNA, which, in turn, is translated into protein, which results in a change of
cell function
Adrenocortical Hormones
Glucocorticoids (GC):
•
Adrenal cortex failure (= Addison’s disease)
缺乏GC 之產生：
–
–
–
–
–
–
•
慢性衰竭、肌肉衰弱Chronic fatigue and muscle
weakness.
食慾喪失，體重減輕
低血壓（hypotension）
Blotchy, dark tanning and freckling of the skin
(這是因為喪失回饋機制feedback missing =>此舉將會造成
corticotropin 濃度上升)
血糖濃度不正常
對於壓力反應不良
Adrenal cortex tumors (= Cushing Syndrome)
GC overproduction
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–
–
–
–
–
–
–
Upper body obesity
“Buffalo hump”
Red, round face
Hypertension
Water retention
Thin skin and bruising
Poor wound healing
Adrenocortical Hormones
Glucocorticoids (GC):
Clinical uses:
•
•
•
•
•
•
•
•
•
•
•
•
•
Allergic Rhinitis
Rheumatoid Arthritis
Asthma
Multiple Sclerosis
Carpal Tunnel Syndrome
Dermatitis
COPD
Osteoarthritis
Gout
Psoriasis
Inflammatory Bowel Disease
Sinusitis
Lupus Erythematosus
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• Many conditions flare up if GC therapy is discontinued due
to adreno-corticol atrophy
Adrenocortical Hormones
Glucocorticoids (GC):
• Hydrocortison (= Cortisol)
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– 人體中主要的糖皮質素
– 可以與 mineralocorticoid receptor 結合之
(但是記住：Cortison 卻不行)
– 可以充當補充治療（針對 ddison’s Disease )
– 大部分都是利用外敷（用） 這是因為該藥物的 sodium-retaining effects
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• Addison‘s disease 細內分泌出現異常所導致。其症狀包括：體重
減輕、疲勞低血壓等。其並因為：腎臟內分泌腺體並沒有生產足
夠的激素如 cortisol ，有時候是所謂的醛固酮（aldosterone），
這些問題我們統稱為 adrenal insufficiency, or hypocortisolism.
• Cortisol ：有數百種生理效應；但最重要的是：協助身體對於壓
力做出適當的反應 ，其效應整理如下：
• 幫助人體維持血壓、以及心血管功能
• 幫助延緩對於免疫系統的反應時間
• 協助平衡胰島素所帶來的效果（對於醣類分子之降解）
• 幫助調控蛋白質、醣類以及脂肪的代謝的調控
• 幫助維持幸福感覺（helps maintain proper arousal and sense of
well-being）
糖皮質素整理
•
•
•
•
•
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•
•
糖皮質素（“glucocorticoid” ）：顧名思義係衍生於該類固醇與葡萄糖代謝有
關。在飢餓狀態（fasted state）中，cortisol將會刺激數種反應，而這些反應皆
可以增加用來維持血糖的濃度
代謝效應（Metabolic effects）：
刺激糖質新生作用（gluconeogenesis），特別是在肝臟中（注意：糖質新生作
用係利用非六碳糖做為原料例如胺基酸、以及甘油此反應對於食肉動物、草食
動物都是很重要的反應），該激素將會刺激糖質新生作用中相關酵素的表現
促進從非肝臟組織中胺基酸的運輸；此舉可以對糖質新生作用產生出正面的幫
助。
I抑制脂肪細胞以及肌肉細胞對於葡萄糖的攝取；此舉可以幫助提升血糖值
刺激脂肪組織中脂肪降解，藉由酯解作用，可以讓肌肉細胞可以利用酯解作用
所產生出脂肪酸（當然將脂肪酸充當能量來源；至於甘油則一如前述可以充當
糖質新生作用的受質）
Adrenocortical Hormones
Glucocorticoids (GC):
• Prednisone
– Inactive until converted to
• Prednisolone
– Drug of choice for systemic application
– Lower sodium-retaining effects
Prednisolone
HO
CH3
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O
O
CH3
Prednisone
OH
OH
O
CH3
O
O
CH3
OH
OH
Adrenocortical Hormones
Glucocorticoids (GC):
HO
CH3
• Triamcinoline
– Stronger anti-inflammatory (5x) than cortisol
– No sodium-retaining effect
HO
CH3
O
O
CH3
OH
OH
CH3
F
O
HO
CH3
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OH
O
O
Halogenated GC
• Betamethasone
• Dexamethasone
– 30x more potent than cortisol
– No water and sodium retaining effects
O
CH3
F
O
O
CH3
OH
OH
CH3
Adrenocortical Hormones
Glucocorticoids (GC):
• Administration
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–
–
–
–
–
Oral
Nasal
Cutaneous
IV
Inhalation
Steroid-based Drugs
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• Sex Steroids
Sex Steroids
• 女性生殖週期（Female reproductive cycle）
– Gonadotropin Releasing Hormone
(GnRH) = Gonadoliberin
刺激以下激素之釋放
另名為：
Luteinizing-hormone releasing hormone
– Follicle stimulating hormone
(FSH) = Follitropin
– Luteinising Hormone
(LH) = Lutropin
此激素可以刺激以下激素的生產
– Estrogens (E) and Gestagens (G)
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此激素將可以輪流進行負控制
– Pituitary (E+G) Hypothalamus (G)
激素生產
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GNRH as a neurohormone
• GNRH as a neurohormone
• GNRH is considered a neurohormone, a hormone produced in a
specific neural cell and released at its neural terminal. A key
area for production of GNRH is the preoptic area of the
hypothalamus, that contains most of the GNRH-secreting
neurons. GNRH is secreted in the hypophysial portal
bloodstream at the median eminence. The portal blood carries
the GNRH to the pituitary gland, which contains the
gonadotrope cells, where GNRH activates its own receptor,
gonadotropin-releasing hormone receptor (GNRHR), a seven
transmembrane G-protein coupled receptor that stimulates the
beta isoform of Phosphoinositide phospholipase C, which goes
on to mobilize calcium and protein kinase C. This results in the
activation of proteins involved in the synthesis and secretion of
the gonadotropins, LH and FSH. GNRH is degraded by
proteolysis within a few minutes.
FSH 與 LH 之控制
•
在腦下垂體， GNRH 將可以刺激促性腺激素（gonadotropins,）
的合成與分泌。分別為濾泡刺激激素以及黃體激素stimulates the
synthesis and secretion of the follicle-stimulating hormone
(FSH) and luteinizing hormone (LH). These processes are
controlled by the size and frequency of GNRH pulses, as well as
by feedback from androgens and estrogens. Low frequency
GNRH pulses lead to FSH release, whereas high frequency
GNRH pulses stimulate LH release.
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•
• There are differences in GNRH secretion between females and
males. In males, GNRH is secreted in pulses at a constant
frequency, but in females the frequency of the pulses varies
during the menstrual cycle and there is a large surge of GNRH
just before ovulation.
Sex Steroids
• Female reproductive cycle
– Cycle length varies from 21-35 days
• Menstruation 3-6 days
– First (= Proliferative) phase:
• Variable (7-21 days)
• FSH and LH promote follicle development
• One follicle becomes the Graafian follicle
(the rest degenerate)
• Graaffian Follicle:
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– Consists of thecal and granulosa cells
which surround the ovum
• FSH-stimulated granulosa cells produce
estrogens from androgen precursors
generated by LH-stimulated thecal cells
• Estrogens are responsible for the
proliferative phase: increase in thickness
and vascularity of endometrium; secretion
of protein+ carbo-rich mucus
• Constant low estrogen inhibits LH/FSH production BUT high estrogen cause
surge of LH production => swellign and rupture of Graafian follicle = Ovulation
Sex Steroids
• Female reproductive cycle
– Second (= Secretory) phase:
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• Secretory phase constant (~ 14 days)
• LH-stimulated ruptured follicle develops
into Corpus luteum which secrets
Progesterone
• Progesterone (Pg) is responsible for the
secretory phase: endometrium becomes
suitable for implantation; mucus thickens
• Thermogenic effects of Pg =>
body temperature increase 0.5º C
• Without implantation: Pg secretion stops
=> menstuation is triggered
• With implantation: continued Pg production
which (via inhibition of LH and FSH prod.)
blocks further ovulation
• Chorion (“precursor” of placenta) secretes
human chorionic gonadotropin (HCG) which
maintains endometrium lining throughout
pregnancy (HCG -> see pregnancy test)
Sex Steroids
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• Female reproductive cycle
Sex Steroids
Estrogens
All produced from androgen precursors
Three main endogenous estrogens:
• Estradiol
–
–
–
–
–
–
–
–
人體中主要雌激素
有關乳癌的發展Breast development
可以改善骨骼密度Improving bone density
子宮發育Growth of the uterus
加速骨骼的成熟以及骨垢閉合Accelerating bone maturation and epiphyses closure
子宮內膜發育以支持懷孕過程的進行
促進陰道黏膜的厚度以及分泌
增加HDLIncrease HDL
• Estrone
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• Estriol
–
僅出現於懷孕過程中（由胎兒製造） (made by fetus)
Sex Steroids
Estrogens
– Estrogens 誘導助孕酮受體表現
– 助孕酮將會抑制雌激素受體（estrogen receptors）表現
– 因此同學需要記住：有兩種雌激素受體可以充當藥物作用標靶
• Estradiol
– 並不能充當口服藥物（因為該藥物將會被肝臟迅速地去除(rapid hepatic elimination)）
=> 擁有穩定的衍生物（stable derivatives）
• Ethinylestradiol
• Diethyl-Stilbestrol
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– Stilbene derivative
Sex Steroids
Estrogens
• Mestranol
– 可以充當口服避孕藥物（ oral contraceptives）
– 本身不具有活性（Inactive） =>
當箭頭所指的 C3-甲氧基（methoxy group ）
將會產生出 ethinylestradiol
• Raloxifene
– Selective estrogen receptor modifier (=SERM)
– Antiestrogenic effects on breast and endometrium
– Estrogenic effects on bone and lipid metabolism
=> use in postmenopausal osteoporosis
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Clinical uses of estrogens:
– Replacement therapy (Turner syndrome; menopause)
– Contraception
– Cancer therapy
Sex Steroids
Anti-Estrogens
• Tamoxifen
– 抗雌激素效應（Antiestrogenic effects ）：
在乳腺組織中出現之
– 其抗雌激素活性較弱（對於骨骼以及脂肪代謝而言）
• Clomiphene
– 抑制雌激素與腦下垂體結合
=>如此一來將會消除所謂的回饋抑制發生
=>排卵發生（ovulation）
臨床上抗雌激素（anti-estrogens）的應用
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– 乳癌治療（Breast cancer therapy） (Tamoxifen)
– 治療不孕症（Infertility） (Clomiphen)
Sex Steroids
Progesterons
• 助孕酮（Progesterone）
– 抑制子宮收縮Inhibits rhythmic contractions of the myometrium
– 並不適合口服（Not suitable for oral administration ）
(肝臟快速分解) =>以下為該化合物的穩定衍生物
（stable derivatives） :
• Hydroxyprogesterone
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• Medroxyprogesterone
Sex Steroids
Progesterons
Testosterone derivatives with progesterone activity:
• Norethindrone
• Norgestrel
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• Desogestrel
Sex Steroids
Anti-Progesterons
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• Mifepristone (RU486)
– 在1980代時發展成功（ French company Roussel Uclaf ）
– 發明過程：在調查糖皮質激素受體拮抗劑（ glucocorticoid receptor
antagonists ）過程中居然讓該科學家發現了與其類似的助孕酮受體拮
抗劑（ blocked the similarly shaped progesterone receptor ），此舉
因而促成RU486的生產 。
– 在1982年，充當墮胎工具（當然實驗室在法國進行）。僅利用一單純
化合物即可誘導出完全的流產（ 80% of women up to 49 days’
gestation ）
– 添加少量的前列腺素類似物（ prostaglandin analogue ），將可以在
數天之後刺激尿道收縮（僅需要上述步驟，其墮胎效果居然達到
100%[該數據為白種人所得；注意：不是台灣人]）
– 在2000在美國被批准在懷孕早期（defined as 49 days or less）進行
墮胎
Sex Steroids
• Male reproductive system
– Gonadotropin Releasing Hormone
(GnRH) = Gonadoliberin
stimulates release of
– Follicle stimulating hormone (FSH)
(Stimulates Sertoli cells =>
promotes gametogenesis)
and
– Luteinising Hormone (LH) =
Interstitial Cell Stimulating Hormone (ICSH)
which triggers production of
– Testosterone (T) (by Leydig cells)
which in turn negatively regulates
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– Pituitary and Hypothalamus hormone production
Sex Steroids
Androgens
• Testosterone
CH3 OH
– 主要的雄性激素
– 擁有雄性激素以及同的發展化作用上的效應 ：
CH3
Androgenic effects:
• 男性雄性器官的生長以及發育
• 對於男性的 sex drive（性慾）以及 performance O
• 第二性徵得發育
Development of secondary sexual characteristics
• 對於精子生成屬重要
Anabolic effects:
• 肌肉質量發育
• 可以逆轉異化反應所帶來的效應
CH3 OH
CH3
• Dihydro-Testosterone
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– 活性的代謝物（Active metabolite）
– 媒介重要的睪固酮作用
O
H
Sex Steroids
Androgens
• Testosterone
R
CH3 OH
– 口服之後將會被肝臟代謝殆盡
– 注射之後，其半衰期短 => ester derivatives:
Proprionate, enanthate, cypionate…
CH3
O
• Fluoxymesterone
– 口服之後將會被肝臟代謝殆盡
Hepatic elimination after oral administration
HO
CH3
F
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O
CH3 OH
CH3
Sex Steroids
CH3 OH
CH3
Anabolic Androgens
Testosterone derivatives: anabolic effects dominant
• Nandrolone
CH3 OH
– Injection
H
O
• Stanozolol
– oral administration
CH3
HN
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N
H
CH3 OH
CH3
O
Sex Steroids
同化雄性激素Anabolic Androgens
• Dehydroepiandrosterone (DHEA)
– 在健康食品店之中市一普遍受到歡迎的項目
僅在不久之前方改為處方項目
– 實際上該化合物為睪固酮前驅物（ testosterone precursor ）
– 如果維持DHEA之血中濃度將有助於維持記憶、活力等年輕的瘦瘦的體態（Oh
!My God!）並中和壓力激素所帶來的負面影響
– 以下才是各位應該更要知道的：DHEA may have serious side effects:
• 如果不尋常地增加睪固酮的濃度，其副作用為：青春痘（ acne ）、睪丸縮小（
testicular atrophy ），罹患前列腺癌的比例大增
• 女性攝取過量的DHEA在文獻上將會有青春痘、臉上長毛髮等
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– DHEA 會在體內轉變為雌激素（estrogen），因此高量的DHEA將會導致雌激素
的副反應等（如女乳症），當然乳癌比例上升
– DHEA 在市場上正被行銷。這是種嚴重的誤導（misleading
Sex Steroids
Anti-Androgens
O
CH3
• Flutamide
HN
CH3
– Non-steroidal receptor antagonist
– 用於前列腺癌治療（prostate cancer treatment）
CF3
NO2
• Finasteride
– Inhibits 5a-reductase =>因此將可以預防睪固酮被轉化為
dihydrotestosterone (DHT)（比睪固酮更具有效果）
– 可以治療前列腺腫大、掉髮等 （因為掉髮患者體內擁有高量的DHT)
O
CH3
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CH3
O
N
H H
N
H
CH3
CH3
CH3
Flutamide 詳細作用機轉
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Flutamide is an oral antiandrogen drug primarily used to treat prostate cancer. It
competes with testosterone and its powerful metabolite, dihydrotestosterone
(DHT) for binding to androgen receptors in the prostate gland. By doing so, it
prevents them from stimulating the prostate cancer cells to grow. Flutamide has
been largely replaced by a newer member of this class, bicalutamide, due to a
better side-effect profile. Flutamide may also be used to treat excess androgen
levels in women. It is marketed by Schering-Plough under the brand name
Eulexin. It is also known as Flutamin
Sex Steroids
GnRH analogs/modifiers
• Danazol
– Inhibits GnRH release => no FSH/LH production
=> no steroid production
– Used to treat endometriosis
(growth of endometrial tissue outside of the uterus)
CH3 OH
CH3
N
O
• Synthetic GnRH (Gonadorelin, Buserelin, Leuprorelin…)
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– 合成的較天然有效200X(than GnRH)
– If given in pulses (s.c.) stimulate gonadotropin release => induce ovulation
– If given continously they desensitize the GnRH receptors => gonadal
suppression (“medical castration”)
– Used in sex hormone-dependent conditions (prostate, breast cancer;
endometriosis; uterine fibroids…)
– Side effects: menopausal symptoms
CH
Danazol
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Danazol is a derivative of the synthetic steroid ethisterone, a
modified testosterone. Also known as 17alpha-ethinyl
testosterone. Before becoming available as a generic drug,
Danazol was marketed as Danocrine in the United States. 係用
來治療子宮內膜異位（在專利藥時期；1970年代）。但該藥物有
嚴重副作用：亦即讓女性產生男性副性徵（ masculinizing sideeffects ）。其扮演角色即為GnRH促效劑（ GnRH agonists ）所
取代。It was approved by the U.S. Food and Drug
Administration (FDA) as the first drug to specifically treat
endometriosis in the early 1970s.[1] Although effective for
endometriosis, its use is limited by its.[2] Its role as a treatment
for endometriosis has been largely replaced by the.
Sex Steroids
Oral Contraceptives
• History
– 1937: Investigators demonstrated that the female
hormone progesterone could halt ovulation in rabbits
– 1949: Scientists at the University of Pennsylvania
achieved the production of synthetic progestins
– 1953: Margaret Sanger, Katherine McCormick and Gregory Pincus team up to
develop a reliable contraceptive
– 1950s: Large scale testing of “the pill” was successful
– 1960: FDA approves first oral contraceptive
(Early pill formulations contained up to 150 micrograms (mcg) of estrogen!)
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– 1982/84: Introduction of the bi- and tri-stage formulation
– 1988: FDA recognized several severe long-term side effects (high estrogen!)
– Currently used by 16 mill. women in the US (40% of women between 18 and 24
Sex Steroids
Oral Contraceptives
Either combination estrogen/progesterone of progesterone alone
• Combination pills:
–
–
–
–
–
Highly effective
Estrogen component is mostly ethinylestradiol, sometimes mestranol
Progesterone component varies
21 day cycle with 7 day break (causes withdrawal bleeding)
Can be mono- or biphasic
Mechanism:
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– Estrogen inhibits FSH secretion (neg. feedback loop!)
=> suppression of follicle development
– Progesterone inhibits LH secretion (neg. feedback loop!)
=> inhibition of ovulation; also increases mucus viscosity
– Both steroids alter endometrium => prevent implantation
Sex Steroids
Oral Contraceptives
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Estrogen
Progesterone
Sex Steroids
Contraceptives
• “Mini Pill”:
–
–
–
–
Contains only a progesterone (Levonorgestrel, Ethynodiol…)
Used when estrogen in contraindicated (e.g. thrombosis)
Taken daily without interruption
Acts mainly by increasing viscosity of mucus
(Mucolytica in cough medicine can cause failure)
– Less reliable than combination pill
• Postcoital contraceptives (“Morning after pill”)
– High dose of progesterone (Levonorgestrel)
– Must be taken within 72 hrs
– Nausea and vomiting are common side effects
• Depot and patch formulations
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– Injection of oily depot formulations every 3 month
– Transdermal delivery systems
Sex Steroids
Oral Contraceptives
Side effects:
–
–
–
–
–
–
–
Thrombosis
Hypertension
Intermittant bleeding
Weight gain
Depression
Nausea
Loss of libido
Drug interactions:
– Steroids are metabolized by P450 enzymes
– Minimal dose of steroid is used to prevent risk of thrombosis
– Any increase in clearance by P450-inducing drugs can result in contraception failure
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– Frequent cause of OC failure is diarrhea (diminished time for absorption)
Evolution of Reproduction Among the Vertebrates
Vertebrate sexual reproduction evolved in the ocean before vertebrates
colonized land
Most marine bony fish use external fertilization
Male and female gametes are released into the water where fertilization
occurs
Most other vertebrates use internal fertilization
Male gametes are introduced into the female reproductive tract

There are three strategies for internal fertilization
1.
2.
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3.
Oviparity

Fertilized eggs are deposited outside mother’s body to complete
their development
Ovoviviparity

Fertilized eggs are retained within the mother to complete their
development

Young obtain nourishment from egg yolk
Viviparity

Fertilized eggs are retained within the mother to complete their
development

Young obtain nourishment from mother’s blood
Three Types of Mammalian Development
– Monotremes are oviparous
• Lay eggs
• Young hatchlings obtain milk by licking mammary glands (they lack
nipples)
– Marsupials are viviparous
• Give birth to incompletely developed fetuses
– Complete development in mother’s pouch
» Obtain food from nipples in mammary glands
– Placentals are viviparous
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• Retain young in uterus for long periods of development
– Fetuses are nourished by the placenta
Mammalian Breeding Patterns
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• Some mammals are seasonal breeders
• Others have reproductive cycles
– Periodic release of a mature ovum (ovulation)
• Most female mammals have estrous cycles
– Females sexually receptive to males only around time of ovulation
(estrus)
• Apes and humans have menstrual cycles
– Females bleed when shedding inner lining of the uterus
– Can copulate at any time in their cycle
• Cats and rabbits are induced ovulators
• Ovulation only after copulation due to LH secretion
如何決定哺乳動物的性別
How Sex is Determined in Mammals
 決定時機：胚胎早期（in embryonic development）即以決定性別
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 胚胎性腺不同；即決定在於Y染色體上的基因：SRY（Sex-determining
region of the Y chromosome）。該基因產物可以將性腺轉變為睪丸。
男性生殖器官
Male Reproductive Organs
• 睪丸（testis ）產生出睪固酮
與精子（sperm）
– Enclosed in a hanging sac
called the scrotum
• 精子發育需要在低溫
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• 精子形成（
spermatogenesis） 在製精
細小管（Seminiferous
Tubules）製造
• 精子將會貯藏於附睪
(Epididymis)並成熟之。
• 從附睪至輸精管（vas
deferens ）至壺腹（ampulla
最長最寬的部份，構成輸卵
管的三分之二，也是受精處  Accessory sex glands:
）
 Empty their secretions into the ducts
• At ejaculation they pass into
during ejaculation
the urethra which empties
 Include the seminal vesicles, prostate
through the penis
gland, and bulbourethral glands
•
精子是在雄性生殖器官－睪丸（testes）內製造的，其會經過
一系列的加工步驟產生而來，此過程包含了：(1)細胞大小的增加
；(2)連續兩次的細胞分裂；(3)使新的細胞由靜止的球體變成細長
可動精子的變態情況。
•
雙套的精原細胞（spermatogonium）會生長轉變成初級精母
細胞（perimary spermatocyte），然後初級精母細胞會進行減數
分裂之第一次分裂，產生兩個單套的次級精母細胞（secondary
spermatocyte），緊接著，每一個次級精母細胞會再進行減數分
裂之第二次分裂，產生兩個精細胞（spermatid）。
•
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之後呢，每一個精細胞會發生蛻變（metamorphosis），即
改變它的外形，由較大而球形而且不動的形狀，演變成較小且細
長而且又可動的精子（sperm）。典型的精子包含頭、中片和尾
等三個部份
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The Testis and Formation of Sperm
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Spermatogenesis
The Male Penis
• The penis contains long
cylinders of spongy tissue
– These get filled with blood
causing an erection
• Physical stimulation is required
for ejaculation
– 2-5 milliliters of semen are
ejected
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• This volume contains
several hundred million
sperm
• Plus secretions from the
prostate and other glands
Mechanism and Effects of Testosterone Activity
• 睪固酮係由膽固醇合成而得
• 該激素必須要運送至目標細胞上發揮其作用
– 前列腺（Prostate ）– 在與細胞核內目標蛋白結合之前，將會轉變為
二羥基睪固酮（dihydrotestosterone (DHT) ）
– 神經元（Neurons） –轉變為雌激素，引起刺激反應
• 睪固酮若缺乏將會引起這些器官的萎縮（atrophy）（至於是哪一
些器官：睪固酮目標器官）
• 雄性激素將會造成青春期（puberty）的出現，並對於非生殖性器
官也會產生影響 ，其效應包括：
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–
–
–
–
–
Appearance of pubic,, axillary （腋窩）以及facial hair
胸部發育、以及聲音變化
皮膚變厚、變油
骨骼生長且密度變高
骨骼肌大小增加，且骨骼質量變大
• 睪固酮無論男女皆是性慾的基礎激素
注意：睪固酮 並不是永遠都會有正確的表現
But It Doesn’t Always Work Right
 身體製造睪固酮，但不意
味著其他的細胞會做出正確
的回應。
 There are cases where the
formation of the Mullerian
ducts is inhibited
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 This leads to the default
development – female
external genitalia
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勒氏管 (Mullerian ducts) 及形成男性生殖道的華爾夫氏管 (Wolffian
ducts)對於生殖系統的影響
生殖道的發育受性染色體基因，導引形成女性生殖道的米勒氏管
(Mullerian ducts) 及形成男性生殖道的華爾夫氏管 (Wolffian
ducts)。性賀爾蒙使性徵更趨明顯。正常狀態下，彼此間的消長
有絕對的排他性。女性的生殖道包括，子宮、輸卵管、陰道等都
是由米勒氏管逐漸成長演變而來。胚胎體腔內左右兩側的米勒氏
管，於發育過程中會逐漸向身體中線交會、融合、形成子宮、子
宮頸、及陰道的雛形。融合的兩側生殖道之間有一間膈，在正常
發育中，這間膈會受基因控制自我溶解消失，終於自動重塑成完
整的女性生殖道：一個子宮、一個子宮頸、一個陰道、兩條輸卵
管。但若這組織成長融合與溶解消退的重塑過程中發生障礙，就
會導致陰道、子宮頸、及子宮的先天異常。
女性生殖道異常的程度與型態有多種形式。間膈的溶解消退不完
全，包括垂直向與橫向間膈的溶解消退不完全。當間膈組織橫向
溶解過程不完全，會導致雙角子宮、雙子宮、雙子宮頸、雙陰道
、雙陰道合併單側閉塞。當間膈組織縱向溶解過程不完全，會導
陰道橫隔閉塞生殖道不通，就是所謂的「石女」。
Female Reproductive Organs
 Ovaries are the primary female
reproductive organs
 Make female gametes (ova)
 Secrete female sex hormones
(estrogen and progesterone)
 Accessory ducts include uterine
tubes, uterus, and vagina
 Internal genitalia – ovaries and
the internal ducts
 External genitalia – external sex
organs
 Labia major (homologous to male
scrotum)
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 Labia minor (homologous to
ventral penis)
 Clitoris (homologous to the penis)
 Erectile tissue hooded by the
prepuce
 The exposed portion is called
the glans
A Comparison of Mammalian Uteruses
• Marsupials, such as opossums, have two unconnected horns, two
cervices and two vaginas
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– Male marsupials have a forked penis!
Events of Oogenesis
•
•
•
•
•
利用卵的減數分裂（meiosis）生
產之
In the fetal period, oogonia (2n
ovarian stem cells) multiply by
mitosis and store nutrients
Primordial follicles appear as
oogonia are transformed into
primary oocytes
Primary oocytes begin meiosis
but stall in prophase I
At puberty, one activated
primary oocyte produces two
haploid cells
– The first polar body
– The secondary oocyte
•
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•
The secondary oocyte arrests in
metaphase II and is ovulated
If penetrated by sperm the
second oocyte completes
meiosis II, yielding:
– One large ovum (the functional
gamete)
The Ovary and Formation of an Ovum
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• At birth, a female’s ovaries
contains all the oocytes she will
ever produce
– 約有200萬的卵母細胞（
oocytes）停頓於第一次減數分
裂的前期I。
– 在青春期時（），由於FSH的釋
放因此造成一些前述的卵母細胞
的再一次的減數分
• 然而，在每一個月經循環中
僅有一個卵細胞會佔有優勢
，！並且被排卵（ovulated
）
• 成熟的卵細胞稱之為 ova
(singular, ovum)
– 此循環每28 天，一次
Fertilization
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• Fertilization of the egg occurs high in the Fallopian tubes (also called
uterine tubes or oviducts)
– The fertilized egg is now called a zygote
• It is transported to the uterus
– A muscular pear-shaped organ about the size of a fist
– It narrows to a muscular ring called the cervix
Fate of the Zygote
• The fertilized egg is pushed down the oviducts by the rhythmic
contraction of its smooth muscles
– The journey takes 5-7 days
• The uterus is lined with a stratified epithelial membrane called the
endometrium
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– The zygote attaches to this layer and begins embryonic development!
• If the egg is not fertilized, the surface layer of the endometrium is shed
during menstruation
– The underlying layer generates a new surface layer during the next cycle
Hormones Coordinate the Reproductive Cycle
The female reproductive cycle is composed of two distinct phases
separated by ovulation
Follicular phase
Egg reaches maturation
Ovulation
Ovary ruptures and releases the egg
Luteal phase
Body continues to prepare for pregnancy
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A family of hormones coordinates these phases
Follicular Phase
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• Development of the egg within the
ovary
• The oocyte and its surrounding
mass of tissue is called the follicle
• FSH secretion triggers the
maturation of several follicles and
resumption of meiosis in their
oocytes
– But only one achieves full
maturity
• FSH also causes the ovary to
secrete estrogen
– Negative feedback by estrogen,
causes the hypothalamus to
stop the pituitary’s FSH output
Luteal Phase
• The body is prepared for fertilization
• Hypothalamus causes the anterior
pituitary to begins secreting
luteinizing hormone (LH)
– LH inhibits further estrogen
production
• It also causes the wall of the
follicles to burst
– Oocyte is ovulated into
oviducts
– LH directs the repair of the ruptured
follicle, which becomes the corpus
luteum
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• The corpus luteum begins to secrete
the hormone progesterone
– Progesterone inhibits FSH
• It also thickens the endometrium
preparing for fertilization
Luteal Phase
• 倘若為完成受精（If fertilization does
not occur）, 助孕酮生產停止。且黃體期
終止。
– 業已加厚的內膜將會脫落（sloughs off ）
– 因此造成月經週期（menstruation cycle）中
的流血This causes the bleeding associated
with
•
倘若受精發生（If fertilization does occur
）, 黃體將會因為人類絨毛膜激素（human
chorionic gonadotropin (hCG)）的作用之下
而得以維持
– hCG 記住：絨毛膜激素係由胚胎所生產之
• 此激素可以在任何的驗孕工具中出現
•
另外兩種激素也是相當重要：
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– Prolactin（泌乳激素）
• 刺激乳汁生產
– Oxytocin（催產激素）
• 啟動乳汁釋放
• 誘導生產過程（Induces labor ）
Luteal Phase
• 整個身體以準備好受孕了
• 下視丘將會引起腦下垂體前葉開始分
泌黃體激素（luteinizing hormone
(LH) ）
– LH 抑制雌激素（estrogen ）的進一步
生產
• 將會引起濾泡壁爆裂（burst）
– 卵母細胞將會排卵（ovulated
）至輸卵管（oviducts）
– LH 將會引導濾泡的修復動作；此種濾
泡將轉變為黃體（corpus luteum）
• 黃體將會開始分泌助孕酮（
progesterone）激素
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– 助孕酮將會抑制濾泡刺激素（
Progesterone inhibits FSH）
• 此激素將會加厚子宮內膜（
endometrium ）厚度以迎接受孕
Events Immediately Following Sperm Penetration
•
•
•
•
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•
Upon entry of sperm, the secondary
oocyte:
– Completes meiosis II
– Casts out the second polar body
The ovum nucleus swells, and the
two nuclei approach each other
When fully swollen, the two nuclei
are called pronuclei
Fertilization – when the pronuclei
come together
The vertebrate embryo develops
in three stages
– Cleavage
• A hollow ball of cell forms
– Gastrulation
• Cells move to the interior,
forming the primary tissues
– Neurulation
• The organs of the body form
•
•
•
•
•
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•
Cleavage: From Zygote to Blastocyst
The first cleavage produces
two daughter cells called
blastomeres
Morula – the 16 or more cell
stage (72 hours old)
By the fourth or fifth day the
preembryo consists of 100 or
so cells (blastocyst)
Blastocyst – a fluid-filled
hollow sphere composed of:
– A single layer of
trophoblasts
– A fluid-filled cavity, the
blastocoel
– An inner cell mass
Trophoblasts take part in
placenta formation
The inner cell mass becomes
the embryonic disc (the
embryo)
Gastrulation: Onset of Developmental Change
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•
Certain groups of cells move inwards from
the inner cell mass at about 10-11 days
after fertilization
– This process of gastrulation results in the
three primary germ layers
• Endoderm
• Ectoderm
• Mesoderm

Neurulation: Determination of Body Architecture
In the third week, the
three primary germ
layers begin
development into
body tissues and
organs
 First, the neural
tube develops from
the ectoderm
 The notochord
develops from the
mesoderm
 The gut develops
from the endoderm

On either side of the notochord blocks of
tissue (somites) form
 These give rise to muscles, vertebrae and
connective tissues developing notochord
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
By the end of the third week, the embryo is
about 2 mm (< 0.1 inches) long
Fetal Development
Fourth week
•
•
•
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•
Organogenesis:
Formation of body
organs,
Critical development
time
Alcohol use may
cause fetal alcohol
syndrome
Embryo reaches
about 5 mm
Second month




Third month
Great changes in

morphology occur
Limbs assume adult
shape
Major internal

organs are evident
Embryo reaches

about 25 mm
Development is
essentially complete
 Except for
lungs and brain
Developing human is
now called a fetus
It carries out
primitive reflexes like
sucking
Second trimester
•
A time of growth
•
Bone formation occurs
•
Hair and body are
covered with fine hair
called lanugo
•
By the end of the 6th
month, the fetus is 30
cm (1 foot) long
Fetal Development & Birth
Third trimester
Post Natal Development

At 1-5 minutes after birth, the
infant’s physical status is
assessed based on five signs:
heart rate, respiration, color,
muscle tone, and reflexes

Babies typically double birth
weight within a few months

Allometric growth: Different
body parts grow at different
rates

Nerve cells produced at an
average rate of > 250,000
per minute

At 6 months, neuron
production ceases
permanently

Pace of growth
accelerates

Weight of fetus more than
doubles

Nutrients are still provided
by mother’s blood via the
placenta

Each observation is given a
score of 0 to 2
Most major nerve tracts
are formed in the brain

Apgar score = the total score
of the above assessments
 8-10 indicates a healthy
baby
 Lower scores reveal
problems

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Apgar Score

Extraembryonic Membranes
The embryo reaches the uterus on day 6
 It penetrates the endometrial lining & initiates membrane formation
 Amnion
 Encloses embryo
 Chorion
 Forms from the trophoblast
 Interacts with uterine tissue to form the placenta
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•
•
•
•
Chorion
Yolk sac
Allantois
Amnion
•
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•
Circulation in Fetus and Newborn
By the end of the 3rd week:
– The embryo has a system
of paired vessels
– The vessels forming the
heart have fused
Unique vascular modifications
seen in prenatal development
include umbilical arteries and
veins, and three vascular
shunts (occluded at birth)
– Ductus venosus – venous
shunt that bypasses the
liver
– Foramen ovale – opening
in the interatrial septa to
bypass pulmonary
circulation
– Ductus arteriosus –
transfers blood from the
right ventricle to the aorta
Effects of Pregnancy
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Anatomical Changes
• Chadwick’s sign – the vagina
develops a purplish hue
• Breasts enlarge and their areolae
darken
• The uterus expands, occupying
most of the abdominal cavity
• Lordosis is common due to the
change of the body’s center of gravity
• Relaxin causes pelvic ligaments and
the pubic symphysis to relax
• Typical weight gain is about 29
pounds
Metabolic Changes
 The placenta secretes human placental lactogen (hPL), also called human
chorionic somatomammotropin (hCS), which:
 Stimulates the maturation of the breasts
 Promotes growth of the fetus
 Exerts a maternal glucose-sparing effect
 Human chorionic thyrotropin (hCT) increases maternal metabolism
 Parathyroid hormone levels are high, ensuring a positive calcium balance
Structure of Lactating Mammary Glands
•
•
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•
•
•
•
Modified sweat glands consisting of 15-25 lobes that radiate around and open
at the nipple
Breast size is determined by the amount of adipose tissue, not the number of
lobes and alveolar glands
Areola – pigmented skin surrounding the nipple
Suspensory ligaments attach the breast to underlying muscle fascia
Lobes contain glandular alveoli that produce milk in lactating women
Compound alveolar glands pass milk to lactiferous ducts, which open to the
outside
Contraception
Several different methods are available
They differ in their effectiveness and
acceptability to different couples
Abstinence & coital timing
Effective if abstinence maintained – statistically risky
Natural family planning, or the rhythm method
Prevention of egg maturation
Birth-control pills
Estrogen and progesterone
Shut down production of the pituitary
hormones FSH and LH
Birth-control injections
Birth-control patches
Prevention of embryo implantation
Intrauterine devices (IUDs)
RU486 (“morning after pill”)
Sperm blockage
Condoms
Diaphragms
Coitus interruptus
Sperm destruction
Spermicidal jellies
Foams
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Sterilization
Vasectomy in males
Tubal ligation in females
Sexually Transmitted Diseases
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• STDs are diseases that are spread from one person to another through
sexual contact
– Common STDs include:
• Genital Herpes
– Caused by the herpes simplex virus type 2 (HSV-2)
– Most common STD in the US
• Chlamydia
– Caused by the bacterium Chlamydia trachomatis
• Genital Human Papillomavirus (HPV)
– Some types cause genital warts
– HPV is a key factor in virtually all types of cervical cancer
• Acquired Immune Deficiency Syndrome (AIDS)
– Caused by the human immunodeficiency virus (HIV)
• Gonorrhea
– Caused by the bacterium Neisseria gonorrhoeae
• Syphilis