Petra De SutterDiv. Reproductive Medicine

UZ Gent

Clinical indications for

androgen assays in gynaecology

Androgens and women

• Source of androgens:– Ovarian theca and stromal cells <LH control

– Adrenal cortex

– Peripheral (< precursors)

• Function?– Estradiol production (aromatisation in granulosa cells <FSH

control)

– Sex drive, muscular mass, etc…

• Which?– DHEA(S) > A’dione > Testo-DHT

• Postmenopauzal:– A’dion mainly adrenal source

17-α-hydroxylase

desmolase

Androgeen productie bij de vrouw in de vruchtbare jaren

Androgeen precursors

DHEAS: Dihydroepiandrosteron sulfaat

DHEA: Dihydroepiandrosteron

A: Androstenedion

TestosteronTestosteron

60%60%

20%20%

90%90%

50%50%

40%40%

25-35%25-35%

50-75%50-75%

ovaria bijnieren

o.i.v. LH o.i.v. ACTH

Totaal T bij de vrouwTotaal T bij de vrouw 1 - 4 1 - 4 nmol nmol/L/L 0,5 - 3 0,5 - 3 nmolnmol/L/L

66% SHBG

Bio-availabletestosteron

30% albumine

Normale verdeling van TNormale verdeling van Tin het bloed van de vrouwin het bloed van de vrouw

CBG CBG CortisolCortisol Binding Globuline Binding GlobulineSHBG SHBG Sex HormoneSex Hormone Binding Globuline Binding Globuline

T is stevig gebonden,dus niet beschikbaar

1,3%vrij T

2,3%CBG

Oorzaken van androgeentekort bij de vrouw

1.Verminderde androgeenproductie

In ovaria: - normale veroudering- bilaterale ovariëctomie- radiotherapie - chemotherapie - GnRH-agonisttherapie

In bijniercortex: - normale veroudering- primaire/secundaire bijnierschorsinsufficiëntie- bilaterale adrenalectomie

In ovaria en bijniercortex: panhypofysaire insufficiëntie

Illustration of the 50% parallel decrease in serum DHEA, DHEA-S, and testosterone between the ages of 21 and 40 years in

healthy women

Oorzaken van androgeentekort bij de vrouw (vervolg)

2. Verhoogde binding van circulerende androgenen aan SHBG → verlaagde vrije androgeenfractie:

- oestrogeentherapie

- (hyperthyreoïdie)

3. Gestoorde androgeenreceptorwerking:

- aangeboren volledige of partiële androgeeninsensitiviteit

- inname van androgeenreceptorblokkeerders: cyproteronacetaat, spironolacton, flutamide

De vrouwelijke seksuele respons: het biopsychosociaal model (R.Basson)

Emotionele intimiteit

Emotionele en fysieke tevredenheid

Zin in seks & verdere arousal

Seksuele stimuli

Arousal

+ +motivatie voor

++

Spontane seksuele honger (drive)

Oxytocine ??

Oestrogenen

Androgenen

Female androgen insufficiency: Princeton consensus (Fertil Steril 2002;77:660-5)

• Symptomen: - verminderd welbevinden en neerslachtige stemming

- blijvende onverklaarde vermoeidheid

- verstoorde seksuele respons (libido)

• Omdat oestrogenen ook een invloed hebben op stemming en seksuele respons, kan de diagnose alleen gesteld worden bij vrouwen met adequate oestrogenisatie

• Vrije testosteronwaarde ≤ 25ste percentiel van normale waarden bij vrouwen tussen 20 en 40 jaar

 

Classification of Female Sexual Dysfunction*

Sexual desire disorders Hypoactive sexual desire disorder Sexual aversion disorder

Sexual arousal disorder

Orgasmic disorder

Sexual pain disorders Dyspareunia Vaginismus

Other sexual pain disorders

*Each disorder is subtyped as lifelong versus acquired, generalized versus situational, and as to etiologic origin (organic, psychogenic, mixed, unknown).

Androgen excess

• Hyperandrogenism

(virilisation)– Acne

– Hirsutism

– alopecia

• Cycle disturbances– PCOS

• HAIR-AN syndrome– Hyperandrogenism

– Insulin resistence

– Acanthosis nigricans

Hyperandrogenism• = any clinical or laboratory evidence of androgen excess in women. • Most common clinical presentation of hyperandrogenism in

reproductive-aged women is hirsutism or acne with or without evidence of anovulation such as oligo- or amenorrhea or dysfunctional uterine bleeding.

• Elevated blood levels of androgens without clinical symptoms is referred to as cryptic hyperandrogenism.

• Hirsutism = presence of course terminal hairs in androgen-dependent areas on the face and body in women >< hypertrichosis =excessive growth of thin vellus hair at any body site (usually familial or associated with anorexia nervosa or thyroid dysfunction, or with medications such as phenytoin, minoxidil or cyclosporin.

• Hirsutism affects 2-10% of women between 18 and 45• Source of psychological discomfort • Scored by Ferriman-Gallwey score

Causes of Hyperandrogenism

Common

Polycystic Ovary Syndrome 80%

Idiopathic Hirsutism 15%

Uncommon

Late-Onset 21-Hydroxylase Deficiency 1-5%

Rare < 1%

Steroidogenic Enzyme Deficiencies 3-hydroxysteroid dehydrogenase 17-ketosteroid reductase aromatase

Androgen Secreting Tumors of Ovary or Adrenal

Ovarian Hyperthecosis (a PCOS variant)

Other EndocrineHyperprolactinemiaCushing syndromeDefects in cortisol metabolismAcromegaly

Evaluation of Hyperandrogenism

History

OnsetProgression

Onset at menarche suggests PCOS, idiopathic hirsutism or 21-hydroxylase deficiency. Onset distinct from menarche suggests tumor.Rapid progression of hirsutism or other symptoms suggests tumor

Physical Examination

Hirsutism and acne Virilization

PCOS or idiopathic hirsutismOvarian or adrenal tumor, hyperthecosis

Laboratory Tests

Total and free testosterone17-hydroxyprogesteroneProlactin, TSH

Confirm hyperandrogenism, rule out tumorRule out mild 21-hydroxylase deficiency. Perform ACTH stimulation test in patients of Askenazi Jewish descent In all patients with oligo-amenorrhea or dysfunctional bleeding

Imaging  

Transvaginal ultrasoundCT of adrenal glands

Confirm polycystic ovaries, rule out ovarian tumorIf ovarian ultrasound is normal and tumor is suspected

PCOS

• heterogenous disease• 5-10 % of all adult women• 20 % of all infertile women• 80-90% of all anovulatory women• criteria for diagnosis (2 out of 3):

PCO image on ultrasound increased androgens (clinically / chemically) irregular cycles

• Validity of Rotterdam consensus?

PCOS

• often (but not always!): obesity insulin resistence (cave diabetes!) increased LH and LH/FSH

• PCO (20%) ≠ PCOS (5-10%)• increased androgens

< adrenal, ovary acne, hirsutism

• irregular cycles -> infertility

cameleon

• symptoms: irregualr cycles: 30-50% amenorrhea: 20-50% hirsutism: 60-70% obesity: 30-40% acne: 30% infertility: 20-70%

• lab: hyperandrogenism: 30-50% increased LH: 40-50%

Normal ovary PCO ovary                                     

Prevalence

• genetic factors: families, twins insulin? Hormone receptors? exogeneous factors

• racial factors Genetic? Food? Surroundings? Asian > mediterranean > Caucasian women

Short term problems

• obesity, acne and hirsutism -> cosmetic problem, psychologic problems, low self image, depression

• irregular cycles -> infertility

• during pregnancy increased risk for miscarriage increased risk for pregnancy diabetes and hypertension

Long term health risks

• obesity -> cariovascular disease, hypertension, myocardial infarction

• insulin resistence -> diabetes• metabolic syndrome or syndrome X

-> obesity, hypercholesterolaemia, atherosclerosis, diabetes

• irregular cycles -> endometrium hyperplasia and cancer

Importance of obesity

• obesity -> does NOT lead to PCOS

• women with PCOS who also are obese have an increased chance to develop symptoms: obesity worsens PCOS !

• weight loss therefore ameliorates PCOS symptomatology

Treatment

• weight loss (>5% often normalizes cycle regularity)• OCS (cycle reg, decreasing androgens)

typically Diane 35 (CA) or Yasmin (drosperinone)

• if child wish: hormonal stimulation• if hirsutism: OCS + CA or cosmetic• metformin ??? Only if IR• dexamethasone >< adrenal androgens• (statins >< lipid disturbances, ovarian androgens)

Life style modification !

TABLE 1. Clinical Impact of Lifestyle Management in PCOS From:   HOEGER: Clin Obstet Gynecol, Volume 50(1).March 2007.277-294

Thank you for your attention