Androgen excess in the postmenopausal woman

Androgen excess in the postmenopausal woman Bronwyn Stuckey ; Department of Endocrinology and Diabetes Sir Charles Gairdner Hospital; School of Medicine and Pharmacology University of Western Australia

Androgen excess in the postmenopausal woman Two basic principles Androgen changes over menopause Sor9ng the physiological from the pathological History Clinical features Inves9ga9ons Management strategies

Basic principles Basic principle no 1 The produc9on of oestrogen goes through an androgen pathway Basic principle no 2 Units of measurement differ 1 micromole = 1000 nanomoles 1 nanomole = 1000 picomoles 1 micromole = 1000000 picomoles DHEAS - µmol Testosterone nmol Oestradiol - pmol

Androgen changes over the menopause v Ovarian factors Increased gonadotrophin drive Loss of oocytes and granulosa cell func9on v SHBG factors Weight gain Insulin resistance v Adrenal factors

LH ACTH insulin T SHBG freet DHT insulin Androgen receptor

Ovarian steroid produc9on begins with androgen produc9on in the theca cell LH R HDL LDL R R ATP Cholesterol camp Androstenedione Granulosa cells Circula*on

Menopause increased gonadotrophin drive and loss of ability to convert to E2 LH R Follicular fluid Circula*on FSH R ATP camp Oestradiol camp ATP HDL R LDL R Cholesterol Aroma9sa9on Androstenedione Androstenedione Theca cell Testosterone Granulosa cell

Adrenal contribu9on to androgens in menopause? Cross- sec9onal studies have shown a downward drir in DHEAS with ageing [Davison JCEM 2005; Santoro JCEM 2005] However, when adjusted for ovarian func9on i.e. stage of menopausal transi9on, there is a rise in DHEAS over the menopausal transi9on [Crawford JCEM 94(8):2945 2951] n = 2886 Mechanism? Decreased clearance or Increased produc9on? driven by rise in gonadotrophins? ovarian or adrenal origin

Changes in SHBG contribute to higher androgen bioavailablity C A SHBG falls with 9me, rela9ve to LMP B Increase in weight contributes to falling SHBG C Free androgen index rises Burger et al JCEM 2000

All mechanisms amplified in postmenopausal women with PCOS Androgen produc9on con9nues Insulin resistance and centripetal weight - > low SHBG Adrenal contribu9on to androgen produc9on Androgen targets primed by prior exposure Dexamethasone suppression demonstrates adrenal origin of androgens in postmenopausal women with PCOS Markopoulos JCEM 2011

Summary so far Loss of oestrogen produc9on Rise in gonadotrophins Upstream androgen produc9on Fall in SHBG All of above lead to increased androgen bioavailability

History taking in hyperandrogenism Menstrual history Does the menstrual history fit with PCOS? Time course of hyperandrogenic symptoms Has there been a premenopausal history of hirsu9sm? Have these appeared during the menopause transi9on? Are they more recent onset? Weight gain Has there been recent weight gain? How does it relate to the onset of androgenic symptoms? Signs that suggest an androgen- secre9ng tumour Voice changes or clitoromegaly Rapid recent onset Cushing s syndrome Weight gain, violaceous striae, proximal muscle weakness, thin skin. Exogenous androgens

Hirsu9sm Hirsu9sm = above 8 in premenopause. No real standard in postmenopause. Note ethnic differences in normal hair distribu9on Note that depilatory methods are usually employed

Androgene9c alopecia hair thinning is very common in women over the age of 50 extent of hair loss does not correlate with circula9ng T levels extent of hair loss does not correlate with distress expressed by pa9ent not so specific as to be a sign of virilisa9on Savin scale 1994

What tests are useful? Testosterone can be ovarian or adrenal origin SHBG low in obesity or insulin resistance or marked androgen excess Calculated free androgen index minor androgens DHEAS Alerts to an adrenal original except in late- onset CAH 17 OH progesterone Alerts to late- onset CAH Morning cor9sol not the best test to do Only useful in excluding Addison s 24 hour urinary free cor9sol OR Midnight salivary cor9sol

History taking in hyperandrogenism is it PCOS? PCOS Signs of hyperandrogenism Hx irregular cycles since puberty Late onset CAH Mrs DB 51y h/o irregular menses and hirsu9sm since puberty 2 children with ART Hx + bilateral oophorectomy to cure PCOS at 30y Rx oral oestrogen and CPA Advised to cease at 50 y Flare of androgenic symptoms Ix FAI = 8.8 (<6.0) 17OHP = 11.1 nmol/l (<2.0)

History taking in hyperandrogenism is it Cushing s Signs of hyperandrogenism New onset Hx regular cycles Striae Weight gain Morning blood cor9sol is of limited value in Dx of Cushing s Use 24h urinary cor9sol or midnight salivary cor9sol as a screening test Elevated 24h urinary cor*sol High ACTH and DHEAS Pituitary MRI Low ACTH Adrenal CT or MRI

History taking in hyperandrogenism is it Cushing s Signs of hyperandrogenism New onset Hx regular cycles Striae Weight gain Elevated 24h urinary cor*sol KH 67 year Normal cycles premenopause 12m h/o hirsu9sm, weight gain Ankle oedema, weakness Central adiposity Thin skin K + 2.3 mmol/l T 2.3 nmol/l (<3.2) FAI 15 (<7.0) DHEAS 6.1 umol/l (0.8-7.0) Androstenedione 33.1 nmol/l (1-12) High ACTH and DHEAS Pituitary MRI Low ACTH Adrenal CT or MRI UFC 21,000 nmol/d (<900) Plasma ACTH 43.3 pmol/l (2-10) Thank you to Dr Ee Mun Lim for this case sumary

History taking in hyperandrogenism is it a tumour? Signs of hyperandrogenism PLUS virilisa*on High T or high DHEAS Adrenal CT or pelvic ultrasound Mrs AT 78 y h/o regular menses 2-3 years facial hirsu9sm, alopecia and deepening voice No HRT use Androgene9c alopecia + hirsu9sm FG score 10 Ix Testosterone 6.6nmol/L (<1.5) FAI 15.6 (<5.5) DHEAS 1.0 µmol/l (<6.0) Imaging no tumour seen T did not suppress with dexamethasone Oophorectomy = Leydig cell tumour Thank you to Dr Jessica Stranks and Dr Peak Mann Mah for permission to use this case history

Diagnos9c algorithm for the inves9ga9on of hyperandrogenism in women arer menopause. Marios C Markopoulos et al. Eur J Endocrinol 2015;172:R79-R91 2015 European Society of Endocrinology

Management strategies Note 1. The use of an9- androgen therapy without contracep9on assumes that the woman is postmenopausal with no chance of conceiving 2. With a few excep9ons pharmacotherapy has diametrically opposite ac9on on hirsu9sm and alopecia

Local measures for hirsu9sm Shaving Cheap Does not increase hair growth Waxing and depiliatory creams may cause folliculi9s and skin irrita9on Photoepila9on IPL and laser Works best on dark hair and fair skin Longer wave laser may be suitable for darker skin Not permanent but longer efficacy Electrolysis Time- consuming

LH ACTH insulin T SHBG freet DHT insulin Androgen receptor

insulin LH T SHBG freet DHT Oral oestrogen + proges9n Oral contracep9ve pill reduces hirsu9sm by 2 mechanisms a) Raising SHBG b) Suppression of LH ACTH Oral oestrogen + proges9n Rx has similar effect Transdermal oestrogen has liole effect on SHBG insulin Use of an an9- androgenic proges9n addi9ve effect MarHn JCEM 2008 Androgen receptor

insulin LH T SHBG freet DHT Spironolactone Mechanism :- a) compe99ve inhibi9on at AR b) 5α- reductase inhibi9on ACTH Aldosterone inhibitor a) urinary frequency b) postural dizziness c) hyperkalaemia is rare Spironolactone 100mg/d v placebo insulin reduced F- G score (- 4.8,95%CI,- 7.4 to- 2.2) MarHn JCEM 2008 Androgen receptor

LH ACTH T Cyproterone acetate insulin An9- androgen proges9n a) Suppresses LH drive b) Competes at AR c) Some reductase inhibi9on d) In higher dose has some glucocor9coid ac9on SHBG freet DHT Androgen receptor insulin

Finasteride + dutasteride 5α- reductase inhibitors LH ACTH Off label use insulin T SHBG freet DHT Finasteride indicated in men for male paoern alopecia Finasteride insulin 5mg reduces F- G scores by 30 60%, as well as reducing hair diameter MarHn JCEM 2008 Androgen receptor

Targeung insulin ac9on

Reducing hyperinsulinaemia One might expect lowering insulin by weight loss or pharmacotherapy to a) reduce ovarian androgen output b) raise SHBG However, placebo controlled studies have shown only modest effect and not as effec9ve LH cf an9androgen therapy ACTH insulin T SHBG freet DHT insulin Androgen receptor

Non- hormonal pharmacological methods Eflornithine for hirsu*sm inhibitor of the ornithine decarboxylase (ODC) ODC ini9ates anagen <1% systemic absorp9on Reduc9on in hair regrowth cf placebo Anagen resumes with cessa9on Minoxidil for alopecia Mechanism is uncertain Promotes growth of hair vellus - > terminal Topical applica9on bd of 2% 5% - > more s/e Oral minoxidil leads to hirsu9sm

LH ACTH insulin T SHBG freet DHT insulin Androgen receptor

Do androgens lead to insulin resistance? Men are more insulin resistant than women [Geer GenderMed 2009] Women with congenital adrenal hyperplasia (untreated with glucocor9coids) have insulin resistance [Speiser JCEM 1992; Saygili HormRes 2005] Gender transi9on female to male engenders insulin resistance [Polderman JCEM 1994] Testosterone Rx leads to insulin resistance in muscle of female rats [Holmang AmJPhysiolEndocrinol 1992] Testosterone produces insulin resistance in female adipocytes [Corbould JEndocrinol 2007]

Summary Menopause enhances androgen produc9on Premenopausal hyperandrogenism is exacerbated post menopause Assessment should aim to dis9nguish Physiological Pathological (neoplas9c or endocrine) Management involves Local measures Hormonal manipula9on at mul9ple target sites