1. The document discusses premature ovarian insufficiency (POI), including delays in diagnosis contributing to low bone density. For every month of delayed diagnosis, spine bone mineral density decreases by 0.026. 2. POI can manifest as delayed puberty, primary or secondary amenorrhea, or irregular periods. Genetic factors are responsible for some cases, with mutations in meiotic and DNA repair genes linked to syndromic and non-syndromic POI. 3. Treatment of POI involves hormone replacement therapy to mimic normal estrogen and progesterone levels. Estrogen therapy should begin at age 12-13 and be gradually increased over 2-3 years. Progestogen is later added for endometrial protection

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PREMATURE OVARIAN INSUFFICIENCY
CURRENT ISSUES
TEVFİK YOLDEMİR MD. BSc. MA. PhD.
tyoldemir
profdrdryoldemir
Human Development Index (HDI)
http://hdr.undp.org/en/content/human-development-index-hdi
Turkey ranks 64 (high HDI)
Subgroup analysis
(HDI categorization, study type and quality )
Data submitted, under review
31 articles; 14 cross-sectional, 17 cohort
Timely diagnosis is vital…
• Often significant delay in diagnosis quoted
o >50% see ≥ 3 clinicians before diagnosis made
o 25% diagnosis > 5 years1
• Delay and subsequent period of estrogen deficiency cited as contributor to low
bone density
• Hormone therapy may not be sufficient to increase bone mass and many lose BMD
by time of FU.2-3
• Better to minimise initial bone loss then try to catch up!
1 Alzubaidi NH et al. 2002 2.Fenton A, J Midlife Health 2015; 3.Bennetti-Pinto Menopause 2015
020406080
Numberofsubjects
< 6 mths 6 mths - 1 yr 1 - 3 yrs 4 - 7 yrs
Time to diagnosis
Panay N, Cucinella L, Gerval M, Maclaran K, Shah G, Banya W 2017
-4-2024
SpineTScore
0 20 40 60 80
Time to Diagnosis (Months)
Measured by Spine T score
Time to delayed diagnosis and its impact on Bone Mineral Density
For every unit increase
in time (month) BMD as
measured by spine t
score decrease by
0.026, p=0.001 (1 way
anova)
Panay N, Cucinella L, Gerval M, Maclaran K, Shah G, Banya W 2017

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Panay N, Cucinella L, Gerval M, Maclaran K, Shah G, Banya W 2017
• POI can manifest as pubertal delay and primary amenorrhea
(PA), secondary amenorrhea (SA), or oligomenorrhea of 4
months.
• Recurrence of menses and pregnancies can occur in up to 22%
of cases with SA for up to 4 months [3], but spontaneous
resumption of follicle activity is exceptional in cases with long-
lasting SA.
• The POI-associated hypergonadotropic hypogonadisms is
defined as elevation of follicle-stimulating hormone (FSH) 25
IU/L confirmed twice, 30 days apart, in women with SA.
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
• The incidence of familial cases of premature ovarian failure was
reported to vary from 4% to 31%.
• Thorough evaluation of alleged affected relatives showed a lower
incidence (12.7%) than the original family history suggested.
• Pedigree studies on affected families showed a mode of inheritance
suggestive of autosomal dominant or recessive transmission with
highly variable expressivity or X-linked inheritance with incomplete
penetrance.
• Approximately 2–6% of women with sporadic POI have a premutation
of the FMR1 gene Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
• The genetic causes of POI are highly heterogeneous, with
isolated or syndromic forms.
• Mutations of meiotic and DNA repair genes are responsible for
syndromic and nonsyndromic POI.
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
Formation of ovarian reserve
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
Genes with in vivo mutations assoc. with POI
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419

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Clinical presentations – Syndromic POI -1
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
Clinical presentations – Syndromic POI -2
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
Clinical presentations – Syndromic POI -3
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
Steps in meiotic recombination
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
Causative genes –oogenesis and folliculogenesis
Trends in Endocrinology & Metabolism, November 2018, Vol. 29, No. 11: 795-807
Causative genes –oogenesis and folliculogenesis
Trends in Endocrinology & Metabolism, November 2018, Vol. 29, No. 11: 795-807

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Next generation sequencing – POI aetiology
Molecular and Cellular Endocrinology 460 (2018) 170-180
Causative genes –whole exome sequencing
Trends in Endocrinology & Metabolism, November 2018, Vol. 29, No. 11: 795-807
Causative genes –whole exome sequencing
Trends in Endocrinology & Metabolism, November 2018, Vol. 29, No. 11: 795-807
Variants identified in candidate genes on the X
chromosome for idiopathic and sporadic POI
Human Reproduction Update, Vol.21, No.6 pp. 787–808, 2015
Variants identified in candidate genes on the X
chromosome for idiopathic and sporadic POI
Human Reproduction Update, Vol.21, No.6 pp. 787–808, 2015
Variants identified in candidate genes on the X
chromosome for idiopathic and sporadic POI
Human Reproduction Update, Vol.21, No.6 pp. 787–808, 2015

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Candidate genes responsible for Mendelian
disorders that manifest POI.
Human Reproduction Update, Vol.21, No.6 pp. 787–808, 2015
Candidate genes responsible for Mendelian
disorders that manifest POI.
Human Reproduction Update, Vol.21, No.6 pp. 787–808, 2015
Genome-wide association studies for POI
Human Reproduction Update, Vol.21, No.6 pp. 787–808, 2015
Treatment -1
• The recommended age for the beginning of oestrogen therapy is
approximately 12-13 years .
• According to the physiology of puberty, in which the oestrogen
concentration is gradually increasing, HRT should be started from
very low doses (6.25 μg/day via patch; 0.25 mg/day orally).
• Various types of oestrogen can be used in the induction of
puberty: oral ethinylestradiol, micronised oestradiol, and
transdermal 17β-oestradiol.
• The preferred therapeutic option is transdermal 17β-oestradiol.
Menopause Rev 2018; 17(3): 135-138
Treatment -2
• Oestrogen doses should be increased every 6-12 months, over
a period of 2-3 years, up to the doses used in adult women
with POI (50-100 μg/day via patch or 1-2 mg/day orally).
• After 2-3 years of oestrogen therapy or when breakthrough
bleeding occurs, progestogen should be added for endometrial
protection, regular withdrawal bleeding, and normal breast and
uterine development.
• The recommended progestogens are: micronised progesterone
(100-200 mg/day) or dydrogesterone (5-10 mg/day) for 12-14
days of the cycle.
Menopause Rev 2018; 17(3): 135-138
Treatment -3
• 1200 mg of calcium and 800-1000 IU of vitamin D per day is
recommended in addition to hormonal replacement in women with
POI.
• Currently available methods of POI therapy include HRT and combined
oral contraceptive (COC).
• HRT, compared to COC, more closely mimics physiological
concentrations of oestrogen and progesterone.
• Oral contraception usually contains ethinyloestradiol, which results in
supraphysiological doses of oestrogen and has an unfavourable effect
on the serum lipid profile and increased production of coagulation
factors. Nevertheless, COC is still a very common form of treatment of
POI patients.
Menopause Rev 2018; 17(3): 135-138

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Treatment -4
• The second generation of synthetic progestogens, such as
levonorgestrel, shows lower risk of VTE compared to recent
generations (gestodene, desogestrel, cyproterone acetate,
drospirenone).
• Physiological sex steroid replacement regimens (transdermal
oestradiol with oral or vaginal micronised progesterone) are
safer than COC in the context of VTE.
Menopause Rev 2018; 17(3): 135-138
Treatment -5
• Ethinyl estradiol (10 mg) is likely to offer an equivalent dose of
estrogen replacement to 1–2mg of estradiol.
• Qlairista (estradiol valerate given in phased doses of 3mg down
to 1mg with dienogest for 26 days followed by 2 inactive pill
days per 28-day cycle) and
• Zoely (1.5 mg estradiol hemihydrate with nomegestrol acetate
for 24 days followed by 4 inactive pill days per 28-day cycle)
both contain estradiol instead of ethinyl estradiol and have an
extended pill taking phase.
Post Reproductive Health 2017, Vol. 23(1) 22–35
Treatment -6
• Suggested replacement doses would be 75–100 mg a day of
transdermal estradiol patches, 2mg equivalent of estradiol gel
(the latter may vary with different products e.g. with
preparations containing 0.6mg per measure, the dose would be
two to four measures a day), 2mg a day of oral estradiol or 10
mg a day of ethinyl estradiol.
• Micronised progesterone and pregnane derivatives as
dydrogesterone may be associated with a lower risk of venous
thromboembolism compared with other progestogens in
particular norpregnane derivatives
Post Reproductive Health 2017, Vol. 23(1) 22–35
• Women with POI have been shown to have lower androgen
levels compared to control groups
• Consideration should be given to androgen replacement,
especially in those suffering from symptoms of testosterone
deficiency, such as reduced libido or lethargy1-3
• Routes
• Transdermal 1-2% gel or 1% testosterone cream 5mg/day
• Subcutaneous implants – unlicensed 50-100mg / 6 months
• Oral DHEA 25mg/d – few data
• Aim for serum testosterone levels within physiological range
to minimise side effects e.g. hair growth and acne (FAI <5%)
Androgen replacement in POI
1.Panay et al Climacteric 2010
2.Maclaran & Panay Women’s Health 2011/2012/2015
3.Achilli et al Fertil Steril 2017
In vitro activation In vitro activation

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In vitro activation In vitro activation
In vitro activation In vitro activation
In vitro activation In vitro activation

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In vitro activation In vitro activation of dormant Follicles
Trends in Endocrinology & Metabolism, June 2018, Vol. 29, No. 6, 400-419
Secure Web-based application
https://poiregistry.net
Digital signature - toconfirmdownloadableconsent
formhasbeensigned
Online form for data entry
Treatment history
Is the biggest challenge for accurate data capture … often large amount
of data!

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Patientid-entirelyanonymous!
(Patientrecordsarenotstoredonregistry:detailsareusedtogenerateuniqueregistry
numbertoavoidduplicationofrecords)
NewPOIGuidelines
NICE
ESHRE
BMS Thank you for your attention.
TEVFİK YOLDEMİR MD. BSc. MA. PhD.
tyoldemir
profdrdryoldemir