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International Medical Scientific Journal        Issue-3 

10.5281/zenodo.5772964 

113 

  



Art of Medicine           Volume-1 

International Medical Scientific Journal        Issue-3 

10.5281/zenodo.5772964 

114 

 

 

 

Art of Medicine International Medical Scientific journal 

 

Founder and Publisher Pascual Izquierdo-Egea 

Published science may 2021 year. Issued Quarterly. 

Internet address: http://artofmedicineimsj.us 

E-mail: info@artofmedicineimsj.us 

11931 Barlow Pl Philadelphia, PA 19116, USA +1 (929) 266-0862 

 

 
  



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Anthropometric, metabolic and bone changes in women with premature ovarian 

failure when using estradiol analogues  
1
Khaidarova Feruza Alimovna, 

2
Fakhrutdinova Sevara Srajitdinovna, 

3
Azizov Bakhodir Sadikovich 

1,2
Republican Specialized Scientific Practical Medical Center of Endocrinology, 

Tashkent, Uzbekistan 
3
Tashkent State Dental Institute, Tashkent, Uzbekistan 

Abstract. Goal. To compare changes in bone, metabolic and anthropometric 

parameters in young women with hypergonadotropic amenorrhea (premature ovarian 

failure [POF], complete androgen insensitivity syndrome [CAIS] with removed 

gonads), undergoing various HT (transdermal estradiol [TE], oral estradiol valerate 

[OEV], oral ethinyl estradiol [OEE] with or without progestin) or without therapy. 

Methods. A pilot cohort study based on prospectively collected data. Bone density, 

body composition and anthropometric parameters were assessed in 40 young women. 

Results. At time t0, only 5% of patients had normal bone mineral density (BMD) in 

all bone regions, while 75% and 20% had osteopenia or osteoporosis, respectively, in 

at least one bone region. Control densitometry (t1) was performed 22.1 ± 9.2 months 

later. Lumbar and femoral BMD increased over time in the treatment groups with a 

significant time-treatment interaction effect (p = 0.004 and p = 0.025, respectively). 

Conclusions. These preliminary data suggest that estradiol is administered both 

transdermally and orally in young women with hypergonadotropic amenorrhea. 

Keywords: bones; hypergonadotropic hypogonadism; amenorrhea; estradiols; 

oral estradiol; transdermal estradiol. 

Introduction. Premature ovarian failure (POF) is a clinical syndrome 

characterized by loss of ovarian activity before the age of 40; this is due to 

hypoestradiolism and oligo- or amenorrhea [1]. POF can have different 

etiopathogenic causes: it can be iatrogenic, as after chemotherapy, radiation therapy, 

or surgery, but it can also be associated with chromosomal / genetic defects (Turner 

syndrome or fragile X syndrome) and with autoimmune disorders, or it may be 

idiopathic [2]. 

Hypergonadotropic amenorrhea also occurs in women with complete androgen 

insensitivity syndrome (CAIS) who have undergone gonadectomy. CAIS is the most 

common sexual development disorder 46, XY, caused by mutations in the androgen 

receptor, causing complete resistance to the action of androgens [3]. 

Both POF and CAIS after gonadectomy are conditions associated with a high 

risk of bone health problems. POF is known to be associated with lower bone density 

than in healthy people [1,4–6] and with an increased risk of fractures at a later age 

[7]. In adolescents and adults with CAIS and remote gonads, there is a decrease in 

bone mineral density (BMD), mainly in the lumbar region; [8-13] however, adequate 

hormone therapy (HT) appears to be able to improve BMD, at least at the lumbar 

level [6,9,11]. 

HT is strongly recommended for women with POF and patients with CAIS 

gonadectomy because it plays an important role in bone protection, as well as in the 



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prevention of cardiovascular disease and mortality [1]. There is still little data on the 

optimal dose, regimen and type of HT in young women with no ovarian estradiol 

production [6,14-17], and, in particular, there are still no data on oral administration 

of estradiol valerate. 

The main objective of this retrospective pilot study was to assess the effect of 

various estradiolic molecules and routes of administration (oral estradiol valerate, 

transdermal estradiol, oral ethinyl estradiol) on bone health in young women with 

hypergonadotropic amenorrhea (idiopathic or iatrogenic POF, women with POF and 

Terner syndrome) and compare them with the results in untreated women. A 

secondary goal of our study was to evaluate the effect of these treatments on the 

biochemical and clinical characteristics of these patients. 

Material and methods 

Study design and population. In this retrospective pilot study, we evaluated 

young adults with secondary hypergonadotropic amenorrhea. The women were 

selected from among the patients who attended the Republican Specialized Scientific 

and Practical Medical Center of Endocrinology named after V.I. J.H. Turakulova. In 

this study, we included women with normal karyotype 46, XX with POF, 

gonadectomized women with SPNA, and women with Turner syndrome. All SPNA 

patients had a 46, XY karyotype with a confirmed androgen receptor mutation and 

previous bilateral gonadectomy, while Turner syndrome patients had a 45, X0 

karyotype. 

For all groups of patients, the following data were recorded: age of onset of 

amenorrhea, age of onset of estradiol intake, type and dose of estradiol, and route of 

administration (oral or transdermal). Age at gonadectomy was also recorded for 

CAIS subjects. Patients were divided into four study groups depending on treatment: 

transdermal estradiol in gel (TE), oral estradiol valerate (EV), oral ethinylestradiol 

(OE) with or without progestin or without treatment (Femur delta BMDs varied 

significantly between groups (p = 0.004), with a significant increase in both TE and 

EV groups compared to OE or E). 

We compared BMD of the spine and hip in these four groups. All patients 

underwent clinical, laboratory and radiological examinations in accordance with 

clinical practice. Anthropometric measurements were carried out on all subjects: 

height was measured with a stadiometer as the distance from the top of the head to 

the floor, when the subject was asked to stand straight, barefoot, touching the walls 

with his shoulders. Body mass index (BMI) was calculated as weight in kilograms 

divided by the square of height in meters (kg / m2). 

Bone parameters were recorded in patient records. BMD was measured using 

dual x-ray absorptiometry. The BMD of the spine was obtained between the lumbar 

levels [1–4] (L1 - L4) and the total BMD of the femur in the femoral neck, 

trochanteric and intertrochanteric regions. The results of measuring the MIC were 

recorded in g / cm2. For BMD, the T-score indicates the extent to which BMD 

measured at a site of bone differs from BMD in a control sample of healthy subjects 

aged [25–30] years (age at which peak bone mass is achieved) ... The World Health 

Organization (WHO) criteria divide BMD T-scores as follows: normal: +2.5 to 1.0 



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standard deviation compared to the mean maximum bone mass in a young person; 

osteopenia: –1 to –2.5 SD and osteoporosis: below –2.5 SD. BMD z-scores, on the 

other hand, refer to the number of standard deviations of values measured at sites of 

bone and how they deviate from values measured in a healthy control population of 

subjects of the same age and sex as the study patients. BMD changes were also 

expressed as deltas (the difference between the two BMD scans. 

The following laboratory test results have been reported: estradiol, LH, FSH, 

fasting glucose, total cholesterol (TC), high and low density lipoproteins (HDL and 

LDL), triglycerides (TG), aspartate and alanine aminotransferase, prothrombin time, 

and activated partial thromboplastin time. All patients were over 18 years of age at 

the time of enrollment. 

Results 

Clinical characteristics of the enrolled women, sixty-two women with 

amenorrhea were potentially eligible and screened. According to our inclusion-

exclusion criteria, 22 women were excluded due to lack of densitometry data. Thus, 

40 women were included in the data analysis. Their average age at the time of the 

first available densitometry assessment (t0) was 23.8 ± 5.5 years (range: 15–35 

years). The etiopathogenetic factors of amenorrhea were distributed as follows: 22 

women with POF, 10 women with Turner syndrome and eight with idiopathic (five 

patients) or iatrogenic POF (three patients after chemotherapy and / or radiation 

therapy for cancer treatment), the latter - 46, XX karyotype. The average duration of 

amenorrhea before the onset of HT was 13.2 ± 4.1 months. 

The clinical characteristics of patients at the time of their first densitometry are 

presented in Tables 1 and 2. At t0 (first densitometry)), 30 patients (75%) did not 

receive hormones, while 10 patients (25%) underwent the first densitometry after 

starting treatment. Smoking rates did not differ between groups. Liver enzymes were 

within the normal range for all included subjects (data not shown). The groups were 

homogeneous, with no significant differences in assessed anthropometric and 

metabolic parameters, with the exception of LDL cholesterol, which showed 

significantly higher levels in EE compared with the EV group (133 ± 41 mg versus 

88 ± 22 mg, p = 0.01) (table 1, 2). 
Table 1  

Baseline anthropometric and clinical parameters of patients included during their first DXA 

scan. 

Parameters  GT (n = 34) BT (n = 6) p 

Increase (years) in t0 24.2 ± 5.4 20.0 ± 6.2 0.093 

GT in t0 (years) (for 

non-accepting GT, n) 

2.6 ± 1.8 (10/34) n.a.  

Height (cm) 58.6 ± 13.6 57.0 ± 13.5 0.792 

Weight, kg) 1.64 ± 0.11 1.61 ± 0.12 0.547 

BMI 21.5 ± 3.8 20.9 ± 3.0 0.719 

Smoking 3 (8.8%) 0 0.999 

Values are expressed as mean ± standard deviation, unless otherwise indicated. BMI, body 

mass index; HT, hormone therapy 

 



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Table 2  

Baseline anthropometric, clinical and bone parameters of the included patients undergoing 

various hormonal regimens. 

Parameters TE (N = 12) EV (N = 15) EV (N = 7) BT (N = 6) R 

Age (years) in t0 24.3 ± 4.4 24.7 ± 5.3 23.0 ± 7.3 20.0 ± 6.2 0.247 

Duration of GT in 

t0 (years) (for 

non-accepting 

GT, n) 

2.3 ± 1.9 

(5/12) 

2.8 ± 1.4 

(3/15) 

3.4 ± 2.8 

(2/7) 

n.a. 0.248 

Height (cm) 59.8 ± 15.6 57.9 ± 12.6 57.7 ± 12.5 57.0 ± 13.5 0.925 

Weight, kg) 1.63 ± 0.11 1.66 ± 0.11 1.63 ± 0.13 1.61 ± 0.12 0.739 

BMI 21.9 ± 4.0 21.3 ± 4.0 21.1 ± 2.7 20.9 ± 3.0 0.944 

Smoking 3 (23%) 0 0 0 0.999 

Δ BMD of the 

lower back (g / 

cm2) (T1-T0) 

0.037 ± 

0.041 

0.064 ± 

0.084 * 

-0.003 ± 

0.073 

-0.078 ± 

0.116 

0.008 

Δ BMD of the 

femur (g / cm2) 

(T1-T0) 

0.026 ± 

0.035 * 

0.026 ± 

0.034 * § 

-0.06 ± 0.06 -0.048 ± 

0.046 

0.004 

Values are expressed as mean ± standard deviation, unless otherwise indicated. BMI, body 

mass index; TE, transdermal estradiol; EV, oral estradiol; EE, oral ethinyl estradiol; NO, no 

hormonal treatment. * = p <0.01 compared with BT; § = p <0.01 compared to EE. 

 

Bone parameters 

Bone parameters during baseline densitometry (t0) 

In the entire cohort, the BMD of the lumbar spine at the first densitometry was 

0.913 ± 0.131 with a T-score of -1.92 ± 1.04 and a Z-score of -1.81 ± 0.98. Femur 

mineral density was 0.865 ± 0.125 with a T-score of -1.06 ± 0.99 and a Z-score of -

1.02 ± 0.90. Taking the entire cohort into account, 30/40 patients (75%) had 

osteopenia and 8/40 (20%) osteoporosis in at least one site of the bone. No 

osteoporotic fractures were found in the study groups. At time t0, the BMD of the 

lower back and hip did not differ significantly between the four groups. In addition, 

most of 10 women already using HT during their first densitometry had BMD 

abnormalities, three patients had osteoporosis (two in the TE group and one in the EV 

group) and six had osteopenia (three in the TE group, one in the EV and one in the 

EE group) in at least one site of the bone. Two had normal BMD in all areas of the 

bone. 

Variations in bone tissue parameters in women receiving different hormonal 

regimens. The time interval between the two estimates of bone mineral density (t1 - 

t0) was 22.1 ± 9.2 months, with no significant differences between the four groups 

(the time interval of densitometry was 20.6 ± 8.9 months for TE, 22.9 ± 9 , 3 months 

for EV, 20.3 ± 8.8 months for EE and 25.0 ± 9.5 months for BT). All HT patients 

reported correct and consistent use of their treatment between the two BMD scores. 

Lumbar BMD showed a significant interaction of time and treatment (p = 0.004]. The 

changes in BMD from t0 to t1 (delta) varied significantly between treatment groups ( 

p = 0.008) .A posteriori analysis revealed a significant increase in lumbar BMD in the 

EV group compared to the BT group (p = 0.006) and in the TE group compared to 



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BT (p = 0.036). In addition, the BMD of the femur showed a significant effect of time 

interaction and treatment (p = 0.025). Changes in BMD from t0 to t1 (delta) 

significantly differed between groups (p = 0.004), with a significant change (increase) 

in BMD of the femur both in the TE and EV groups compared to BT or with EE. 

Anthropometric and metabolic parameters 

BMI at baseline was within normal limits and the same in all groups. BMI and 

metabolic parameters (glucose, total cholesterol, HDL and LDL cholesterol, 

triglycerides and liver enzymes) did not show significant changes in patients 

receiving and not receiving therapy. Blood pressure was within normal limits and did 

not change during the study period. 

Discussion. In this pilot study, we compared changes in bone, metabolic, and 

anthropometric parameters in very young women with hypergonadotropic 

hypogonadism, POF, and CAIS receiving different hormonal regimens (oral estradiol 

valerate, transdermal estradiol, oral ethinyl estradiol, or no hormonal therapy). 

Although our results should be validated in a larger sample, both transdermal and oral 

estradiol appeared to be associated with large short-term improvements in bone BMD 

compared with ethinyl estradiol or no therapy. 

During their first densitometry, the entire cohort presented T-scores indicative 

of osteopenia, in particular for the lumbar region, but also for the femur, with only 

five percent of patients having normal BMD in all areas of the bone. The second 

BMD study was performed 22.1 ± 9.2 months after the first. Both oral estradiol 

valerate and transdermal estradiol were associated with significant increases in 

lumbar BMD and changes in femur BMD, significantly different from those obtained 

with oral ethinyl estradiol or no treatment. In women who received oral 

ethinylestradiol or did not receive treatment, there was a slight decrease or no 

significant changes in BMD. 

No significant changes in anthropometric and metabolic parameters were 

observed during the treatment period, even though the small sample size may have 

limited the detection of differences. 

POF and CAIS are known risk factors for bone health. Several studies have 

shown that women with POF have lower BMD and a significantly increased risk of 

fractures [7,18,19]. Long-term HT can reduce the increased risk of fractures [4,17,20-

22]. In particular, a major health concern for very young women with POF is that 

potentially long-term estradiol deficiency at a young age can lead to a decrease in 

peak bone accumulation in the event of delayed or inadequate HT [4]. Likewise, it is 

known that women living with CAIS have low BMD both before and after 

gonadectomy due to a combination of estradiol deficiency and bone resistance to 

androgens, and in some cases due to inadequate HT after gonadectomy [9,11, 12]. 

The lumbar spine is more prone to BMD deficiency, as it is characterized by a 

predominance of trabecular bone. Recently, it was confirmed that HT-containing 

estradiols are able to increase BMD in this area, but not on the femoral neck [6, 20] 

Research on optimal hormonal treatment for women with POF and CAIS is 

still limited. In our cohort, the transdermal route was confirmed to be superior to oral 

ethinyl estradiol in improving BMD in the lumbar and femoral regions. Transdermal 



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estradiol administration has already been associated with better BMD in women with 

POF compared to both conjugated oral estradiols and oral ethinylestradiol [15,21]. In 

the CAIS population, the transdermal route of estradiol administration appears to be 

superior to oral administration in terms of increasing total body mineral density [6]. 

Although the sample size is limited, our study appears to show that oral 

estradiol valerate is superior to oral ethinyl estradiol in increasing BMD in the lumbar 

and femoral regions. This is the first study to show the ability of oral administration 

of 2 mg estradiol valerate with or without progestin to increase BMD more than oral 

administration of ethinyl estradiol plus progestin: the increase in BMD in the lumbar 

spine was the same as with transdermal estradiol. and even more than that obtained 

transdermally in the femoral neck. 

There are limited but consistent data on estradiol in this population: Cartwright 

et al. In a two-year, open-label, randomized trial reported the superiority of estradiol 

2 mg (plus 5 mcg levonorgestrel for 12 days per month) over 30 mcg ethinyl estradiol 

(plus levonorgestrel). 150 mcg taken daily for 21 days a month) to increase BMD of 

the lumbar spine in women with spontaneous POF [17]. 

Some limitations of this study should be noted. First of all, POF at this young 

age and CAIS are rare conditions; for this reason, a small cohort was analyzed in this 

pilot study, and this could lead to a statistical error of type II. In addition, various 

etiologies of amenorrhea were included in the analysis. In addition, some statistically 

significant associations should be interpreted with caution given the small number of 

subjects in each group. Another limitation is the retrospective nature of the study. The 

two BMD evaluations were performed on the same machine for each patient, but the 

cohort as a whole used different machines. 

In conclusion, these preliminary data suggest a superiority of oral estradiol 

valerate over oral ethinyl estradiol in improving lumbar and femoral BMD in young 

women with hypergonadotropic hypogonadism. In accordance with previous 

literature, our cohort of women with POF and CAIS was characterized by some 

violation of the BMD, in particular, at the level of the lower back. After 22.1 ± 9.2 

months, treatment with oral estradiol valerate or transdermal estradiol showed the 

ability to induce positive changes in the lumbar and femoral regions, while women 

who received oral ethinyl estradiol or did not receive any treatment showed little or 

no significant changes in BMD. Further research in larger cohorts is imperative to 

understand which hormone treatment is best for bone health in young women with 

POF or CAIS, as there is little data available on optimal molecules, regimen, and 

dosages. 

  



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