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Premature ovarian insufficiency -novel hormonal approaches in optimizing

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optimizing fertility

Article in Gynecological Endocrinology · July 2019

DOI: 10.1080/09513590.2019.1640203

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Premature ovarian insufficiency – novel hormonal

approaches in optimizing fertility

Svetlana Dragojević Dikić, Mladenko Vasiljević, Ana Jovanović, Srdjan Dikić,

Aleksandar Jurišić, Ljubomir Srbinović & Svetlana Vujović

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novel hormonal approaches in optimizing fertility, Gynecological Endocrinology

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GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2019.1640203

ORIGINAL ARTICLE

Premature ovarian insufficiency – novel hormonal approaches in

optimizing fertility
Svetlana Dragojevic Dikica, Mladenko Vasiljevica, Ana Jovanovica, Srdjan Dikicb, Aleksandar Jurisica,
Ljubomir Srbinovica and Svetlana Vujovicc
a
Medical Faculty, University of Belgrade, Gynecology-Obstetrics Clinic “Narodni Front”, Belgrade, Serbia; bUniversity Medical Center “Bezanijska
kosa”, Belgrade, Serbia; cMedical Faculty, University of Belgrade, Clinic of Endocrinology, Clinical Center of Serbia, Belgrade, Serbia

ABSTRACT ARTICLE HISTORY

Premature ovarian insufficiency (POI) is a delicate medical problem in young women. This condition is Received 21 May 2019
not unchangeable and permanent but is associated with intermittent and unpredictable ovarian activity, Accepted 2 July 2019
resulting in low conception rate. Over the period of 8 years, the evaluation of secondary amenorrhea was Published online 17 July
conducted in 90 patients below the age of 40 who wished to restore fertility. Having confirmed the diag- 2019
nosis and investigated the etiology of POI, hormone replacement therapy was applied (sequential admin- KEYWORDS
istration of estradiol and norethisterone acetate) in the first 30 patients (group A). Estrogen–progestogen Premature ovarian
therapy with daily supplementation of 25 mg of micronized oral dehydroepiandrosterone (DHEA) was insufficiency; hormone
conducted in 44 patients (group B), whereas a combined regime (estrogen–progestogen therapy, DHEA therapy; dehydroepiandros-
supplementation in daily dose of 25 mg, and melatonin supplementation in daily dose of 3 mg) was con- terone; melatonin; fertility
ducted in 16 patients (group C). In the course of our study, 16 pregnancies were realized (18% of all
cases: 17% in group A; 18% in group B; 19% in group C) 6 to 20 months after the initiation of hormone
therapy, and there have been 13 completed term pregnancies so far with normal fetal growth and devel-
opment. We concluded that estrogen–progestogen therapy combined with DHEA and melatonin could
optimize fertility and lead to successful pregnancy in POI patients.

Introduction enables ovarian function recovery by promoting folliculogenesis

and conception. Estrogen may increase the number and sensitiv-
Premature ovarian insufficiency (POI) generally describes a syn-
ity of FSH receptors in the granulosa cells and start recruitment
drome consisting of amenorrhea or olygomenorrhoea for at least of follicles [8]. In most of the cases, ovulation seems to occur in
4 months, sex steroid deficiency (estradiol below 50 pmol/L) and women whose serum FSH concentrations are suppressed to
elevated levels of gonadotropins [follicle stimulating hormone below 15 IU/L [9]. Either short course or long-term estrogen
(FSH) above 40 IU/L on two occasions more than 4 weeks apart] administration has been found to be useful in POI patients lead-
before the age of 40 [1]. Infertility and psychological stress are ing to successful pregnancy [10].
common consequences of this entity with prevalence of 1–3% DHEA, one of the most important neurosteroids has been
[2]. POI is highly heterogeneous condition that may have widely used in women with POI or reduced ovarian reserve and
chromosomal, genetic, enzyme deficiencies, of autoimmune, iat- poor responders to ovarian stimulation, in a daily dose
rogenic or idiopathic origin [3]. This delicate state in young 25–75 mg. The postulated mechanisms of its benefits are
women is not unchangeable and permanent due to the presence increased intraovarian androgen level; increased number of FSH
of residual egg cells that are capable of being recruited and fertil- receptors expressed in the granulosa cells; increase in insulin-like
ized. It is estimated that approximately 5–15% are able to con- growth factor 1 (IGF-1), which can promote the gonadotropin
ceive spontaneously [1,2]. However, pregnancy in POI patients is effect; increased numbers of preantral and small antral follicles;
still unlikely and rare; hence patients are advised to use donated increased angiogenesis at the level of tubes and follicles;
gametes or embryos [4]. Many patients will not accept oocyte or improvement of the quality of oocytes as well as embryo ploidy
embryo donation as a first-line treatment, but they would rather [11]. Genazzani provided an overview of DHEA actions on
seek other treatment choices. whole women’s body [12].
Different treatment modalities have been discussed, and on Melatonin, a universal photoperiodic hormone is a small lipo-
selected occasions those that might improve reproductive outcome in philic indoleamin, which is primarily released at night by the
patient with POI were proposed: hormone replacement therapy pineal gland. [13]. It can be synthesized by virtually all the cells
(HRT), i.e. estrogen–progestogen therapy; immunosuppression with containing a nucleus. Beneficial effects of melatonin on repro-
glucocorticoids; ovarian stimulation with clomiphene citrate and ductive functions are predominantly realized by: reducing con-
gonadotropin therapy; dehydroepiandrosterone; melatonin [1,3,5–7]. centrations of highly reactive hydroxyl radicals from the oocytes
Not only does an adequate and individualized hormonal ther- and the embryo; promoting antioxidant enzymes and gene
apy treat the consequences of estrogen deficiency, but it also expression; increasing levels of estradiol and progesterone;

CONTACT Svetlana Dragojevic Dikic [email protected] Medical Faculty, University of Belgrade, Gynecology-Obstetrics Clinic “Narodni
Front”, Kraljice Natalije 62, 11 000 Belgrade, Serbia
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2  DIKIC
S. DRAGOJEVIC  ET AL.

Table 1. Characteristics of POI patients.

A B C
Group Median IQR Median IQR Median IQR p Valuea
Age (years) 37 32–40 36 30–39 35 31–38 .521
BMI (kg/m2) 23 19–25 22 19–24 22 18–25 .657
Age at menarche(years) 13 12–15 12 11–14 13 12–14 .498
FSH (IU/L) 85.5 52.6–110.4 60.5 40.6–100.2 62.5 42.6–82.6 .127
LH (IU/L) 48.7 32.4–63.6 46.6 30.4–65.5 42.5 30.4–58.5 .439
Inhibin B (pg/ml) 15.2 10.5–20.2 18.2 12.5–22.2 19.8 15.5–24.2 .231
E2 (pg/ml) 11.9 8.5–38.2 10.9 9.5–35.2 12.7 9.5–39.2 .647
AMH (ng/ml) 0.15 0.06–0.41 0.16 0.04–0.34 0.20 0.03–0.40 .256
Prolactin (ng/ml) 7.5 5.5–20.5 9.2 6.8–22.5 8.5 6.5–18.5 .744
TSH (mIU/L) 1.65 0.92–2.65 1.85 0.88–2.45 1.75 0.82–2.55 .459
fT4 (ng/L) 13.5 10.7–16.9 14.8 11.7–16.8 13.8 11.7–15.9 .293
IQR: interquartile range; BMI: body mass index; FSH: follicle-stimulating hormone; LH: luteinizing hormone; E2: estradiol; AMH: anti-Mullerian hormone; TSH: thyroid-
stimulating hormone; fT4: free thyroxin.
Data were summarized as median with interquartile range for continuous variables.
a
ANOVA test compared between groups.

stimulating production of maturation-inducing hormone (MIH) first 30 patients (group A). Estrogen–progestogen therapy with
in oocyte [14] Clinical studies support positive effects of mela- daily supplementation of 25 mg of micronized oral dehydroepian-
tonin on oocyte and embryo quality, on fertilization and preg- drosterone (DHEA) was conducted in 44 patients (group B),
nancy rate, and patients with subfertility, infertility, even those whereas a combined regime with melatonin (estrogen–progestogen
with POI may benefit from melatonin supplementation [15,16]. therapy, DHEA supplementation in daily dose of 25 mg, and
melatonin supplementation in daily dose of 3 mg) was conducted
in the third group of 16 patients (group C). All patients in the ref-
Materials and methods erence groups gave informed consent regarding the performed
Subjects and study design investigations and treatment.

This retrospective study was performed at the Gynecology-

Obstetrics Clinic “Narodni Front”, Medical Faculty, University of Statistical analysis
Belgrade and at the Clinic of Endocrinology, Clinical Center of
Obtained data were analyzed using methods of descriptive and
Serbia, Medical Faculty, University of Belgrade, Serbia. Over the
analytic statistics. Processed data are presented in tables.
period of 8 years, the evaluation of secondary amenorrhea was
Student’s t test, Chi-square test, and ANOVA test were applied
conducted in 90 POI patients below the age of 40 who wished to
for statistical analysis. We used IBM SPSS software for statis-
restore fertility. The exclusion criteria were the following:
tical analysis.
patients with secondary causes of POI, such as surgery, chemo-
therapy or radiotherapy, and chromosomal abnormalities,
patients who have used oral contraceptives or HRT. Results
We collected the following data for each study patient: age;
body mass index (BMI); hormone analyses including: FSH, This study included 90 patients divided into three groups.
luteinizing hormone (LH), estradiol (E2), inhibin B, anti- Idiopathic cause was detected in 82 patients (89% of POI
Mullerian hormone (AMH), prolactin, thyroid-stimulating hor- patients). Immunological involvement was present in 8 POI
mone (TSH), free thyroxin (fT4); ultrasonographic and Doppler patients, according to the elevated levels of thyroid peroxidase
parameters of ovaries and endometrium including: ovarian vol- antibodies (>10 IU/ml; Roche), but without hypothyroidism, and
ume of both ovaries, antral follicle count (AFC), stromal blood elevated levels of antiovarian autoantibodies (>10 IU/ml; Roche).
flow at the level of both ovaries, by means of evaluation of resist- Comparing characteristics in these groups, such as age, BMI,
ance index values (RI) and pulsatility index values (PI), and age of menarche, as well as endocrinological findings, no differ-
endometrium thickness. Autoimmune screen for polyendocrino- ences were found in any of the observed characteristics (p > .05).
pathies was also performed. It is safe to presume that all patients had similar although low
Hormone analyses were tested using chemiluminescence fertility potential (Table 1).
immunoassay (CLIA), with reagents provided by Abbott (Abbott Analysis of ultrasonographic and Doppler characteristics has
Ireland Diagnostics, Lisnamuck, Longford, Ireland), and ultra- also shown equal distribution among the three groups (Table 2).
sonographic examinations with Doppler studies of hemodynamic No differences were found regarding ovarian volume, AFC, stro-
parameters (RI, PI) were carried out with a General Electric mal blood flow, and other Doppler markers, between groups A,
Voluson S6 computed ultrasound device. B and C (p > .05).
Having confirmed the diagnosis of POI, HRT was promptly In all three study groups, pregnancy was realized in 16 (18%)
started. All the POI patients sought pregnancy, but did not accept out of 90 patients (17% in group A; 18% in group B; 19% in
oocyte or embryo donation as a first-line treatment. Taking into group C) 6 to 20 months after the initiation of hormone therapy.
consideration that resumption of ovarian activity is possible in There have been 13 completed term pregnancies so far with 3
POI women and that different treatment modalities might restore ongoing pregnancies. Serial ultrasonographic measurements, as
ovarian activity in those women, patients were divided in three well as Doppler hemodynamic parameters confirmed normal
reference groups, searching for the “ideal” treatment approach for growth indices of the fetuses, without malformations. Comparing
possible spontaneous pregnancy achievement. Sequential adminis- results in groups A, B, and C there was no statistically significant
tration of estradiol and norethisterone acetate was applied in the difference in the number of pregnant patients (p > .05), although
 GYNECOLOGICAL ENDOCRINOLOGY 3

Table 2. Ultrasonographic and Doppler parameters of ovaries and endometrium of POI patients.
A B C
Group Median IQR Median IQR Median IQR p Valuea
Ovarian volume (cm ) 3
–
Right ovary 2.6 2.2–3.5 2.5 2.2–3.0 2.7 2.1–3.2 .137
Left ovary 2.8 2.3–3.7 2.9 2.1–3.5 2.9 2.0–3.6 .168
AFC 4 0–7 3 1–6 4 0–8 .885
SBF –
Absent 18 (60%) 24 (54%) 8 (50%) .186
Present in 1 ovary 8 (27%) 14 (32%) 5 (31%) .112
Present in both ovaries 4 (13%) 6 (14%) 3 (19%) .227
RI –
Right ovary 0.59 0.55–0.68 0.56 0.50–0.67 0.55 0.50–0.60 .088
Left ovary 0.61 0.56–0.65 0.62 0.56–0.68 0.60 0.55–0.69 .105
PI –
Right ovary 0.96 0.90–1.10 0.95 0.88–1.15 0.94 0.89–0.99 .713
Left ovary 0.94 0.90–0.98 0.93 0.90–0.96 0.92 0.90–0.98 .549
Endometrium (mm) 2.8 2.3–3.5 2.6 2.2–3.2 2.9 2.3–3.7 .141
AFC: Antral follicle count; PI: Pulsatility Index; RI: Resistance Index; SBF: Stromal blood flow.
Data were summarized as median with interquartile range for continuous variables.
a
ANOVA test compared between groups.

Table 3. Pregnancy outcomes in POI patients. intermittent, rather than completely impaired “wave of follicular
Group A B C p Value a development” (OPOI); short window of opportunity for initia-
Pregnancy realized Yes 5 (17%) 8 (18%) 3 (19%) .980 tions of hormone therapy after confirming the diagnosis; com-
No 25 36 13 bined hormonal regime that could create better precautions to
a
Chi-square test was used in the comparison for dichotomous variables. improve reproductive outcome in POI patients with more or less
significance [21].
a slightly higher pregnancy rate was obtained in group B, and in Hormone therapy has been proved to have a positive effect
particular group C, compared to group A. Small number of on follicuogenesis and subsequent conception. HRT is thought to
patients in group C doesn’t compromise the strength of statis- lower gonadotropin levels into a physiologically normal range,
tical analysis (Table 3). and subsequently the FSH receptors are up-regulated and
restored [10]. Estradiol directly sensitizes and differentiates gran-
ulosa cells, stimulates endometrial proliferation, improves vascu-
Discussion larization and endometrial flow, being beneficial for both, ovary
and well prepared endometrium, which is essential for pregnancy
POI is a heterogeneous condition and one of the most challeng-
achievement [9].
ing problems in reproductive medicine. It is a difficult diagnosis
Results from our study confirmed that no significant differen-
for women to accept, in particular for those for whom fertility is
ces emerged between the groups regarding pregnancy achieved,
a priority. Therefore, a carefully planned and sensitive approach
although slightly higher pregnancy rate was obtained in group B
is required when informing patients of the diagnosis, and when
(“DHEA” group), and in particular group C (“melatonin” group),
searching for the most appropriate treatment strategy.
compared to group A. Numerous hypotheses have been made on
In the majority of cases the cause is idiopathic, and it was so
how DHEA promotes fertility. Besides serving as an essential
in our study as well having 89% patients with an unknown cause
of POI. Immunological involvement was present in 8 POI pro-hormone in ovarian follicular steroidogenesis, facilitating fol-
patients. Thyroid autoimmunity is the most prevalent (25–60%) licular function and growth, DHEA seems to increase follicular
associated endocrine autoimmune abnormality reported in POI IGF-I concentrations, probably independently of changes in
patients without an adrenal autoimmune involvement [17]. growth hormone (GH) secretion [11]. Kokcu pointed that DHEA
Antiovarian autoantibodies are usually considered to be a suit- was an effective first step treatment of POI [9]. In recent years,
able and independent marker of autoimmune ovarian disease the majority of in vitro fertilization (IVF) centers in the world
that might predict future ovarian failure in women with unex- have started to use DHEA supplementation in poor responder
plained infertility, although their specificity and pathogenic role patients, and the best results are obtained after four to five
are questionable [18]. months of supplementation with 50–75 mg of micronized DHEA
POI condition is not necessarily permanent, but is associated daily, a time period similar to the complete follicular recruitment
with intermittent and unpredictable ovarian activity. This state cycle [22].
in particular has been seen in the stage that might precede POI, Melatonin has a significant impact on the female reproductive
defined as ovarian function deviation that derives from prema- system. It is huge radical scavenger in follicles, being essential
ture exhaustion of primordial follicles, with some menstrual for folliculogeneis, steroidogenesis, oocyte maturation, ovulation,
competency, and called occult premature ovarian insufficiency corpus luteum function, and early embryo development [7,23].
(OPOI) [19]. In our study relatively higher rate of pregnancies Studies showed that melatonin treatment in a 3 mg daily dose
was achieved, compared to previous studies [1,2,4,9]. improved fertilization rate, pregnancy rate and embryo develop-
Spontaneous pregnancies have been reported to be 5–15% [1,20]. ment in infertile patients who underwent in vitro fertilization
Several explanations could support higher rate of spontaneous and embryo transfer (IVF-ET) program [24]. Melatonin might
pregnancies in our study: patients with partially preserved ovar- be a promising candidate for the treatment of POI, by reducing
ian function, according to AMH levels, AFC, and the presence of oxidative stress and apoptotic damage via activation of silent
stromal blood flow at the level of one of both ovaries; information regulator 1 (SIRT1) in a receptor-dependent manner
4  DIKIC
S. DRAGOJEVIC  ET AL.

[25] More data confirm melatonin’s cytoprotective effect, [10] Dragojevic Dikic S, Rakic S, Nikolic B, et al. Hormone replacement
together with immunomodulatory one that would seem essential therapy and successful pregnancy in a patient with premature ovarian
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[11] Artini PG, Pinelli S, Papini F, et al. Supplementation with dehydroe-
for the success of pregnancy and correct fetal development [14].
piandrosterone as a promising treatment for poor responders. J
Major finding from the study showed that estrogen–progesto- Fertiliz in Vitro. 2011;1:1–5.
gen therapy combined with DHEA and melatonin could improve [12] Genazzani AR, Pluchino N. DHEA therapy in postmenopausal
fertility outcome in POI patients. Indeed, it is with interest that women: the need to move forward beyond the lack of evidence.
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Professionals’ dedicated mission is crucial for this sensitive group ductive organ health and melatonin: ready for prime time. Int J Mol
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Disclosure statement
logical insight into premature ovarian failure (POF). Autoimmunity
No potential conflict of interest was reported by the authors. Rev. 2010;9:771–774.
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