26.2008 reproductive endocrinology

Zhang Huiying

Normal and Abnormal Menstruation

Reproductive Endocrinology

Main contents

• Normal manstruation

• Abnormal uterine bleeding★• Amenorrhea ★• Perimenopause and perimenopausal

syndrome

• polycystic ovarian syndrome(PCOS)polycystic ovarian syndrome(PCOS)

Normal menstruation Mean interval is 28

days +/- 7 days. Mean duration is

2~7 days. More than 7 days

is abnormal. Average blood loss

with menstruation is 35-50 ml. More than 80 ml is abnormal

CNS-Hypothalamus-PituitaryOvary-uterus Interaction

Hypothalamus

Gn-RH

Ant. pituitary

FSH, LH

Ovaries

Uterus

ProgesteroneEstrogen

Menses

–± ?

CNSNot clear

The normal menstrual cycle is the result of complex interactions between the hypothalamic- pituitary-ovarian (HPO) endocrine axis.

Hypothalamus secrete gonadotropin-releasing hormone, The anterior pituitary release the FSH and LH Every cycle the ovary change from follicular development phas

e to the luteal phase secrete estrogen and progesterone The endometrium change from proliferative phases to secretory

phases. When progesterone and estrogen levels fall with the demise of the corpus luteum, vasoactive substances such as prostaglandins, histamine and bradykinin are produced by the endometrium. Prostaglandins cause spasm of the spiral arterioles which results in ischaemic necrosis and shedding of all but the basal layer of the endometrium.

The control of regular menstrual blood loss

• vasodilatation of spiral arterioles

• fibrinolytic activity of menstrual blood

• endometrial regeneration.

Abnormal uterine bleeding

Sorts of bleeding• Abnormal menstrual bleeding

• Other causes

pregnancy

Systemic disease

Cancer

Patterns of abnormal uterine bleeding• Menorrhagia(hypermenorrhea)

• Hypomenorrhea

• Metrorrhagia(intermenstrual bleeding)

• Polymenorrhea

• Menometrorrhagia

• Oligomenorrhea

• Contact bleeding(postcoital bleeding)

Menorrhagia

• Menorrhagia is heavy or prolonged menstrual flow. It is defined as menstrual blood loss exceeding 80 ml per cycle. Submucous myomas ， adenomyosis ， IUDs ， endometrial hyperplasias ， malignant tumors ， and dysfunctional bleeding are causes of menorrhagia.

Hypomenorrhea

• Hypomenorrhea is unusually light menstrual flow ， sometimes only spotting.

• cervical stenosis and Uterine synechiae （ Asherman's syndrome ） can be causative

Metrorrhagia

• Metrorrhagia is bleeding occurring at any time between menstrual periods.

• Ovulatory bleeding occurs at midcycle as spotting

Polymenorrhea

• Polymenorrhea describes periods that occur too frequently, less than 21 days apart. This is usually associated with anovulation and rarely with a shortened luteal phase in the menstrual cycle.

Menometrorrhagia

• Menometrorrhagia is bleeding that occurs at irregular intervals. The amount and duration of bleeding also vary.

• Sudden onset of irregular bleeding episodes may be an indication of malignant tumors or complications of pregnancy.

Oligomenorrhea

• Oligomenorrhea describes menstrual periods that occur more than 35 days apart.

• Bleeding is usually associated with anovulation

Contact bleeding(postcoital bleeding)

• Contact bleeding must be considered a sign of cervical cancer until proved otherwise.

Evaluation of abnormal uterine bleeding• History• Physical examination• Cytologic examination• Endometrial biopsy• Saline hysterosonogram• Hysteroscopy• Dilatation and curettage(D ＆ C)• Other diagnostic procedures(assay hC

G,pelvic ultrasonography,laparoscopy)

History• the amount of menstrual flow • the length of the menstrual cycle and men

strual period• the length and amount of episodes of inter

menstrual bleeding• any episodes of contact bleeding. • the last menstrual period ， the last norma

l menstrual period• age at menarche and menopause• any changes in general health.

Physical examination• Abdominal masses and an enlarged ， irre

gular uterus suggest myoma.• A symmetrically enlarged uterus is more t

ypical of adenomyosis or endometrial carcinoma.

• Atrophic and inflammatory vulvar and vaginal lesions can be visualized

• cervical polyps and invasive lesions of cervical carcinoma can be seen.

• Rectovaginal examination is especially important sometimes

Cytologic examination-cytologic smears

A very useful method to screen the asymptomatic intraepithelial lesions.

Endometrial biopsy

• the Novak suction curet

• the Duncan curet

• the Kevorkisn curet

• the pipelle.

Saline hysterosonogram• Ultrasound followi

ng injection of saline into the uterus has been used to evaluate the endometrial cavity for polyps ， fibroids ，or other abnormalities.

Hysteroscopy• Hysteroscopy Pl

acing an endoscopic camera through the cervix into the endometrial cavity allows direct visualization of the cavity.

Dilatation and curettage(D＆ C)

• D ＆ C is the gold standard for the diagnosis of abnormal uterine bleeding.

• Curettage of the endocervix should be performed before sounding of the endometrial cavity or dilatation of the cervix is done.

Other diagnostic procedures

• assay hCG

• pelvic ultrasonography

• laparoscopy

abnormal uterine bleeding due to gynecologic diseases and disorders

• Vulva and vagina --atrophic vulvitis or vaginitis

• Cervix – eversion, cervical polyps, cervical cancer

• Uterus –endometritis, hyperplasias, cancer, submucous myomas,IUD

• Ovaries—estrogen-producing tumor, other cancers

Abnormal bleeding due to nongynecologic diseases and disorders

• Severe hypothyroidism

• Liver disease

• Blood dyscrasias and coagulation abnormalities

• Use anticoagulants or adrenal steroids

Dysfunctional uterine bleeding(DUB)

definition★• Dysfunctional uterine bleeding(DUB)

is irregular, abnormal uterine bleeding with no demonstrable organic causes. That is not caused by a tumor, infection, or pregnancy. It may be occur during postmenarchal and perimenopausal periods in a woman's reproductive life.

• Exclusion of pathologic causes of abnormal bleeding establishes the diagnosis of DUB

DUB occur in

before the menopause(50%)

after menarche(20%)

reproductive times(30%)

EtiologyEtiology of DUB: of DUB:

1. 1. disorders ofdisorders of hypothalamus---pituitary ---ovary axishypothalamus---pituitary ---ovary axis immature of feedback regulation in young womenimmature of feedback regulation in young women ovarian function failure in premenopause womenovarian function failure in premenopause women

2.other Factors:2.other Factors: the effects of sex hormones the effects of sex hormones nervousnervous Circumstance changeCircumstance change PCOS,TSHPCOS,TSH↑,PRL↑↑,PRL↑ excessive physical exerciseexcessive physical exercise

MechanismsMechanisms

have developing folliculi have developing folliculi no mature follicle no mature follicle no corpus luteumno corpus luteum only have estrogen, but no progestionly have estrogen, but no progesti

n n breakthrough bleeding, spotingbreakthrough bleeding, spoting

pathologic Changes in the endometrium

• Endometrial hyperplasia

Simple hyperplasia

Complex hyperplasia

Atypical hyperplasia• Proliferative phase endometrium• Atrophic endometrium

Treatment

• Depends on the age of patient

Adolescent

Young woman

Premenopausal woman

Adolescent• Acute hemorrhage :high-dose estroge

n given intravenously or injection (25mg conjugated estrogen every 4h)

• Hemodynamically stable patients: take oral conjugated estrogen (2.5mg every 4-6h) or take oral contraceptives 3-4 times the usual dose.

• ★Lower the dose every 3 days for 1/3 dose after the bleeding stoped and when have lowered to an usual dose, give medroxyprogesterone acetate (MPA)10mg once or twice a day for 10-14d

2.5mg / 6h2.5mg / 6h

2.5mg / 8h2.5mg / 8h2.5mg / 12h2.5mg / 12h

2.5mg / d2.5mg / d

Use to

bleeding stoped

3d

3d3d

1.25mg / d1.25mg / d

10-14d

medroxyprogesterone acetate 10-14dmedroxyprogesterone acetate 10-14d

• Next 3-6 months give cycling theraphy

Sequential hormones

Oral contraceptive

Adolescent

Young women

• Except the pathologic causes is necessary

• Hormonal management is the same as for adolescents

• Oral contraceptives may be used as normally prescribed if the patient don’t desire for childbearing

• Induce ovulation if necessary

Premenopausal women• More care should be given to excludi

ng pathologic causes because of the possibility of endometrial cancer

• Aspiration ,curettage,or both should clearly establish anovulatory or dyssynchronous cycles as the cause before hormonal therapy is started.

• Recurrences of abnormal bleeding demand further evaluation

Surgical measures• D ＆ C:temporarily stop bleeding

• Conservative surgery: endometrial ablation or resection using diathermy ,thermal (ballon, microwave..etc.)or laser.

• Hysterectomy :whose lifestyle is compromised by persistence of irregular bleeding,coexistent endometriosis, myoma, other disorders of pelvic

polycystic ovarian polycystic ovarian syndrome(PCOS)syndrome(PCOS)

BACKGROUNDBACKGROUND In 1935, Stein and Leventhal published a paIn 1935, Stein and Leventhal published a pa

per on their findings in seven women with aper on their findings in seven women with amenorrhea, hirsutism, obesity, and a charamenorrhea, hirsutism, obesity, and a characteristic polycystic appearance to their ovacteristic polycystic appearance to their ovaries — one of the first descriptions of a comries — one of the first descriptions of a complex phenotype today known as the plex phenotype today known as the polycystpolycystic ovary syndromeic ovary syndrome. The condition is now we. The condition is now well recognized as having a major effect throull recognized as having a major effect throughout life on the reproductive, metabolic, aghout life on the reproductive, metabolic, and cardiovascular health of affected women.nd cardiovascular health of affected women.

Clinical ManifestationsClinical Manifestations Menstrual dysfunction- oligomenorrhea or amenMenstrual dysfunction- oligomenorrhea or amen

orrhea orrhea Hyperandrogenism -hirsutism, acne, male patterHyperandrogenism -hirsutism, acne, male patter

n balding or hair lossn balding or hair loss Ovarian Morphology- Polycystic ovaries be seen oOvarian Morphology- Polycystic ovaries be seen o

n ultrasonography n ultrasonography Infertility Infertility Obesity and insulin resistance -At least one-half oObesity and insulin resistance -At least one-half o

f women with PCOS are obese and with insulin ref women with PCOS are obese and with insulin resistance sistance

Biochemical Abnormalities-elevated serum andrBiochemical Abnormalities-elevated serum androgen levels,LH/FSHogen levels,LH/FSH≥≥2.5~3, hyperinsulinemia , Sl2.5~3, hyperinsulinemia , Slightly elevated prolactin. ightly elevated prolactin.

HirsutismHirsutism Excessive body hair. In Excessive body hair. In

women with PCOS darwomen with PCOS dark, coarse hair will appk, coarse hair will appear on the face, neck, cear on the face, neck, chest, arms, and in bethest, arms, and in between the legs.ween the legs.

AcneAcne Because women witBecause women wit

h PCOS are producih PCOS are producing more male hormng more male hormone, that produces one, that produces more sebum ( skin omore sebum ( skin oils and old tissue) anils and old tissue) and causes blocked pod causes blocked pores and more acne ares and more acne around the jawline, around the jawline, arms and chest.rms and chest.

Alopecia or Female Pattern BaldAlopecia or Female Pattern Baldnessness

This is caused by the This is caused by the increase of male horincrease of male hormone in the womemone in the women's body. Thinning on's body. Thinning or loss of hair is usualr loss of hair is usually contained to top oly contained to top of the scalp, but in sevf the scalp, but in severe cases loss of hair ere cases loss of hair in front or on the haiin front or on the hairline has been docurline has been documented.mented.

““Dirty Skin” or Acanthosis NigDirty Skin” or Acanthosis Nigricansricans

This condition causThis condition causes light brown to bles light brown to black rough patches aack rough patches around the neck and round the neck and under arms.under arms.

Clinical featuresClinical features OligomenorrhoeaOligomenorrhoea 30-50%30-50% AmenorrhoeaAmenorrhoea 20-50%20-50% HirsutismHirsutism 65-70%65-70% AcneAcne 27-35%27-35% AlopeciaAlopecia 3-5%3-5% InfertilityInfertility 20-75%20-75% OverweightOverweight 40% 40%

but obesity increases severity but obesity increases severity therefore those worst affected are therefore those worst affected are likely to be obeselikely to be obese

Diagnostic Criteria of Diagnostic Criteria of PCOSPCOS

after the exclusion of related disorders, after the exclusion of related disorders, by two of the following three features:by two of the following three features:

1) oligo- or anovulation; 1) oligo- or anovulation; 2) clinical and/or biochemical signs o2) clinical and/or biochemical signs o

f hyperandrogenism; f hyperandrogenism; 3) polycystic ovaries. 3) polycystic ovaries. expert conference held in expert conference held in Rotterdam in May 2003 Rotterdam in May 2003 defined PCOSdefined PCOS

Long term risks of PCOSLong term risks of PCOS

Type 2 diabetesType 2 diabetes Cardiovascular diseaseCardiovascular disease InfertilityInfertility MiscarriageMiscarriage Gestational DMGestational DM Endometrial cancerEndometrial cancer

Mechanism of PCOSMechanism of PCOS

Complicated anComplicated and unclearly knowd unclearly knoweded

TreatmentTreatment

If pregnancy is desired ------ induce ovulaIf pregnancy is desired ------ induce ovulation tion

anti-estrogens(clomiphene)anti-estrogens(clomiphene) GonadotropinsGonadotropins insulin-lowering agentsinsulin-lowering agents anti-androgens (agents that lower anti-androgens (agents that lower androgen levels)androgen levels) gonadotropin releasing hormone gonadotropin releasing hormone agonists (GnRHa)agonists (GnRHa)

If pregnancy is not desiredIf pregnancy is not desired

to reduce the risk of endometrial cancer ( birtto reduce the risk of endometrial cancer ( birth control pills)h control pills)

anti-androgens.anti-androgens. cyclical progesteronecyclical progesterone (MPA, Provera)(MPA, Provera) insulin-lowering agentsinsulin-lowering agents (metformin ,Glucoph(metformin ,Glucoph

age)age)

TreatmentTreatment