Monthly Archives: April 2019

Ultrasonographic Changes in Fascial Properties over Time after Myofascial Release

DOI: 10.31038/IJOT.2019214

Abstract

Recently, ultrasonic imaging modalities have been increasingly used to observe the locomotor apparatus. Furthermore, a high reliability has been reported for the measurements of fascial displacement using ultrasonic imaging and of muscle stiffness using ultrasonic elastography. This study aimed to clarify the ultrasonographic changes in fascial displacement and muscle stiffness induced by Myofascial Release (MFR). We divided 51 healthy adults (24 males and 27 females) into three groups: MFR, Static Stretching (SS), and control groups. The passive ankle joint dorsiflexion angle, isometric ankle joint flexor muscle strength, superficial- and deep-layer fascial displacement, and muscle stiffness were each measured before, immediately after, and at 4 days after an intervention. All parameters in the MFR group showed significant changes immediately after and 4 days after the intervention compared with those at baseline. The MFR group also showed more significant changes in the dorsiflexion angle, fascial displacement, and muscle stiffness after 4 days compared with the SS group. Thus, MFR improves the viscoelasticity of the gelled matrix and eliminates the densification of collagen and elastin fibers, thereby smoothing fascial gliding. Consequently, this technique may help to regain the gliding ability of the fascia during joint movement and muscle contraction. In addition, it was also suggested that changes in physical function and fascial property due to MFR were significantly different after 4 days.

Keywords

Myofascial Release, Static Stretching, Fascial Displacement, Muscle Stiffness, Changes Over Time

Introduction

The fascia is a tissue which envelops the whole body on the sheath from head to toe and is continuous from the surface of the soft tissue to the visceral organ. One of the main functions of the fascia is to support the organs, and in addition to supporting blood vessels, nerves, and lymphatics, it passes through them. Therefore, when a functional abnormality (such as densification of collagen and elastin fiber, gelation of matrix, aggregation of hyaluronic acid) occurs in the fascia, symptoms such as pain, malalignment, limited range of motion, or muscle output weakness are manifested [1]. Myofascial release (MFR) is a manual therapy used to treat fascial dysfunctions, such as dysfunctions, including collagen and elastin fiber densification, matrix gelation, and hyaluronic acid agglomeration, by continuously applying gentle pressure and extension to the deep fascia [1]. We previously investigated the immediate and long-term effects (6 days) of MFR for the hamstrings based on the straight-leg-raising angle and the knee flexion muscle strength. Significant increases were noted in both the angle and the strength until 4 days after MFR, [2] but the outcome was only verified by a change in physical function, it was unknown what changes occurred in the fascia, and it was not possible to explain what benefit fascia was actually giving.

Ultrasound is a noninvasive imaging method with easy utility that can be used to observe the locomotor apparatus. For example, Chi-Fishman et al. [3] and Maganaris et al. [4] reported high reliability with a positive correlation between ultrasound and the change in physical function. Fukunaga et al. [5] also observed changes in the pennation angle of the fascia and muscle bundle under voluntary contraction and reported that changes in muscle bundle length and pennation angle on ultrasound could be quantified for use in physiological and biomechanical research. These findings indicate that it is reasonable to use ultrasonography to observe fascial displacement (gliding). Indeed, Otsudo et al. [6] used ultrasound to visualize the fascia of the gastrocnemius during voluntary contraction, and Ichikawa et al. [7] reported that there was significant movement of the fascia of the vastus lateralis during knee flexion under voluntary contraction or passive exercise conditions. The reliability of ultrasonic imaging of the fascia was confirmed by Ichikawa et al. [8] for the vastus lateralis and by Murano et al. [9] for the tibialis anterior, with both showing high reliability without addition or proportional errors.

Elastography is another ultrasound method and can be used to measure muscle stiffness, with strain elastography most widely used because it can be applied simply and in real-time [10]. The intra-rater reliability of muscle stiffness measurement by strain elastography is reportedly very high [11–12]. Therefore, we used strain elastography to examine the intra- and inter-rater reliabilities at baseline and day 4 for measurements of muscle stiffness (0° ankle joint) and displacement of the superficial and deep fascia of the lateral head of the gastrocnemius during passive ankle dorsiflexion. The intraclass correlation coefficients indicated that reliability was almost perfect (0.89–1.00) [13,14]. Therefore, this method has high validity and high reproducibility for measuring fascial displacement and muscle stiffness of the lateral head of the gastrocnemius up to 4 days after MFR.

We wanted to use ultrasound equipment to visualize fascial gliding with high reliability to investigate the changes in fascial properties over 4 days. To clarify whether changes develop in the fascia after MFR, we assessed the effect of MFR on the fascia by observing not only changes in physical function but also the ultrasonographic changes in fascial displacement and muscle stiffness at baseline, immediately after, and at 4 days after MFR.

Methods and Materials

Study Design and Participants

This study included 51 healthy adults (24 males and 27 females) in their 20s and 30s who had no history of orthopedic diseases of legs, cardiovascular diseases, or central nervous system diseases. The average age (range) was 27.6 (22–37) years, the average height (standard deviation) was 162.9 (7.08) cm, and the average body weight (standard deviation) was 56.6 (9.34) kg. The participants were quasi-randomly distributed into an MFR group, a Static Stretching (SS) group, and a control group.

The study was approved by the Research Safety Committee of Tokyo Metropolitan University (approval number 17110), the Research Ethics Committee of Saku University (approval number 217004), and the Clinical Research Ethics Review committee of Asama General Hospital (approval number 17–18). All participants received an explanation of the purpose and content of the study and we obtained written informed consent.

Protocol

For the MFR group, a practitioner placed his or her hands on the proximal and distal portions of the lateral head of the gastrocnemius of the pivoting foot in the prone position and MFR was performed in the longitudinal direction for 180 s (Figure 1). For the SS group, the foot was taken out of the bed in the prone position and placed on a plantarflexion strength measuring aid (Takei Instrumentation Co., Ltd.). The trunk and foot are fixed by using the shoulder pad, pedal, and pelvic belt of this aid with the knee and the ankle joint at 0°. Then, passive dorsiflexion of the ankle joint was performed three times of resting for 60 s by turning the lever at the angle not causing compensation or pain (Figure 2). For the control group, participants were laid prone on the bed for 180 s and subject to no intervention. The participants were asked not to engage in any special exercise during the 4 days of the study, but they were encouraged to continue with daily life as usual.

Measurements

The following items were measured: (1) passive ankle joint dorsiflexion angle (“angle”), (2) isometric ankle joint flexion strength (“strength”), (3) superficial and deep fascial displacement, and (4) muscle stiffness. All items were measured in the prone position with feet taken out of the bed, the knee and the ankle joint at 0°, and the trunk and foot fixed with the shoulder pad, pedal, and pelvic belt of the plantarflexion strength measurement aid. Two or three people performed each measurement so that the participants were not informed of the group to which they were assigned. Each measurement was performed in triplicate before, immediately after, and 4 days after an intervention, and the average at each assessment was used. The measurement procedures are now presented in more detail.

IJOT 19-109 Yasuki Katsumata_F1

Figure 1. Myofascial release of the lateral head of the gastrocnemius.

IJOT 19-109 Yasuki Katsumata_F2

Figure 2. Method of passive dorsiflexion of the ankle joint.
(By turning the lever, the pedal is dorsiflexed and the triceps surae is stretched)

(1) Angle measurement

We used the sensors of a biaxial goniometer for the ankle joint (SG110 / type A manufactured by DKH Co., Ltd.) attached to a feedback recording device (PH-7010 Feedback Logger manufactured by DKH Co., Ltd.) placed on the fifth metatarsal bone and fibula (Figure 3). Passive ankle joint dorsiflexion was performed mechanically from a joint position of 0° using the plantarflexion strength measurement aid, and the maximum dorsiflexion angle within tolerable pain limits was measured.

IJOT 19-109 Yasuki Katsumata_F3

Figure 3. The procedure for measuring the range of motion.
A: The position of the electronic goniometer B: The mechanical passive ankle dorsiflexion

(2) Strength Measurement

This was measured at maximum isometric ankle joint plantarflexion by applying a sensor of a manual muscle strength measuring device (μTas F-1 manufactured by Anima Co., Ltd.) between the first metatarsal head and the pedal of the plantarflexion strength measurement aid (Figure 4). The value obtained was multiplied by the lever arm to obtain the joint torque value, before being divided by body weight.

IJOT 19-109 Yasuki Katsumata_F4

Figure 4. Positioning of the foot and sensor for strength measurement.
(The sensor position (arrow) of the measuring device for manual muscle force during isometric plantarflexion)

(3) Superficial and Deep Fascial Displacement

A linear probe with a coupler attached at the tip (EZU-TEATC 1 manufactured by Hitachi Aloka Medical, Co., Ltd.) was placed on the lateral head of the gastrocnemius of the pivoting foot, parallel to the long axis of the lower thigh. We marked the edge of the coupler attachment with a permanent marker so that the probe could be repeatedly applied to the same site. Passive ankle dorsiflexion was performed from 0° to 15° using the plantarflexion strength measuring aid, and we visually tracked the displacement of the intersection of the gastrocnemius muscle fiber and the superficial and deep fascia on the screen of an ultrasound (Noblus, manufactured by Hitachi Aloka Medical, Ltd.) (Figure 5) and measured it. We took great care to use minimum contact strength to ensure clear ultrasonic images without changes in muscle shape.

IJOT 19-109 Yasuki Katsumata_F5

Figure 5. Representative ultrasound images.
A: Intersection of the gastrocnemius muscle fiber and the superficial fascia. A’: Point A after passive dorsiflexion. B: Intersection of the gastrocnemius muscle fiber and the deep fascia. B’: Point B after passive dorsiflexion.

(4) Muscle Stiffness Measurement

SONA GEL (N0511 manufactured by Takiron Co., Ltd.) at a thickness of 5 mm was sandwiched between the probe and the skin when comparing muscle stiffness. We used the real-time tissue elastography setting and applied pressure several times on the part assessed in the measurement of fascial displacement at a prespecified level to identify the appropriate pressure. The strain ratios for the regions of interest were calculated for the SONA GEL (Figure 6A) and the gastrocnemius (upper, lower, left, and right central parts depicted on the screen) (Figure 6B).

Measurements and recordings were performed by 2–3 persons so that the subjects were not informed about the group to which they were assigned (PROBE method). Each measurement was performed 3 times: before, immediately after, and 4 days after the intervention, and an average value (three significant figures) was adopted.

Statistical Analysis

We used IBM SPSS Version 22 (IBM Corp., Armonk, NY, USA) for the statistical analyses. To compare physical features between the three groups, one-way analysis of variance was performed for the basic attributes (i.e., age, height, and weight of each group) and baseline measurements (i.e., before intervention) after confirming the normality of that data. The differences between groups at each measurement point and the differences between each measurement point in each group were analyzed using the Dunnett and Bonferroni methods after repeated measures analysis of variance with the basic attributes set as covariates. The significance level was set at 5%. Descriptive data are presented as mean (range) or as mean (standard deviation).

IJOT 19-109 Yasuki Katsumata_F6

Figure 6. Representative image of real-time tissue elastography.
A: Region of interest for SONA GEL (reference) B: Region of interest of for the gastrocnemius

Results

Basic Findings

The MFR, SS, and the control groups each included eight men and nine females. There were no differences in physical characteristics among the three groups before the intervention (Table 1). However, we did observe interactions between groups for each measurement item and at each measurement period immediately and 4 days after MFR. Tables 2–5 show the changes in each measurement item over time by study group.

Table 1. Baseline physical characteristics of each group.

IJOT 19-109 Yasuki Katsumata_F7

Data are shown as the mean (standard deviation) before intervention. Range is only reported for the age. Abbreviations: MFR, myofascial release; SS, static stretching. The control group received no intervention and simply lay on a bed for the same duration as used for SS and MFR.

Changes in the angle

There was a significant increase in the angle in the MFR group immediately and 4 days after the intervention compared with before the intervention; by contrast, the SS group showed a significant increase only immediately after the intervention. There were no significant differences in values between the MFR and SS groups immediately after the intervention, but the differences tended to be larger in the MFR group after 4 days (Table 2).

Table 2. Time course of the changes in angle (°) measurements.

IJOT 19-109 Yasuki Katsumata_F8

Mean (Standard deviation). *: P < 0.05; **: P < 0.01; †: 0.05 ≤ P < 0.1;
: represents the result of the Dunnett method. Abbreviations: MFR, myofascial release; SS, static stretching. The control group received no intervention and simply lay on a bed for the same duration as used for SS and MFR.

Changes in Strength

Strength increased significantly in the MFR group immediately and 4 days after the intervention compared with before, but decreased significantly in the SS group immediately after the intervention. The MFR group only showed significantly higher strength than the SS group immediately after intervention (Table 3).

Table 3. Time course of the changes in strength measurements (N∙m/kg).

IJOT 19-109 Yasuki Katsumata_F9

Mean (Standard deviation). *: P < 0.05; **: P < 0.01;
: represents the result of the Dunnett method. Abbreviations: MFR, myofascial release; SS, static stretching. The control group received no intervention and simply lay on a bed for the same duration as used for SS and MFR.

Changes in Fascial Displacement

In both the superficial and the deep layers, fascial displacement in the MFR group increased significantly immediately and 4 days after the intervention compared with before. However, the SS group only showed a significant increase immediately after the intervention. The results were comparable between the MFR and SS groups immediately after the intervention, but after 4 days, the MFR group tended to show greater displacement in the superficial layer and showed significantly greater displacement in the deep layer (Table 4).

Changes in Stiffness

Regarding the stiffness, the MFR group showed a significant decrease immediately and 4 days after the intervention compared with before, whereas the SS group showed a significant decrease only immediately after. The MFR group had significantly less stiffness than the SS group both immediately and 4 days after the intervention (Table 5).

Table 4. Time course of the changes in displacement (mm) measurements.

IJOT 19-109 Yasuki Katsumata_F10

Mean (Standard deviation). *: P < 0.05; **: P < 0.01; †:0.05 ≤ P < 0.1;
: represents the result of the Dunnett method. Abbreviations: MFR, myofascial release; SS, static stretching. The control group received no intervention and simply lay on a bed for the same duration as used for SS and MFR.

Table 5. Time course of the changes in muscle stiffness measurements.

IJOT 19-109 Yasuki Katsumata_F11

Mean (Standard deviation). *: P < 0.05; **: P < 0.01;
: represents the result of the Dunnett method. Abbreviations: MFR, myofascial release; SS, static stretching. The control group received no intervention and simply lay on a bed for the same duration as used for SS and MFR.

Discussion

We predicted that MFR would produce significant differences in physical function (angle and strength) and fascial properties (displacement and muscle stiffness) immediately and 4 days after the intervention compared with that at baseline and that those changes would be larger than those observed when performing SS. Consistent with our previous research, [2] we noted significant improvements in physical function in the MFR group compared with those in physical function in the SS and control groups at both post-intervention assessments. However, the angle tended to be higher after 4 days, with no significant difference in strength, whereas our previous data indicated that both the angle and strength continued to significantly improve until 4 days [2]. The gastrocnemius muscle has medial and lateral heads, which are semi-pennate muscles, and this muscle may account for the different results observed between our studies.

In the previous study, we performed MFR on the posterior aspect of the thigh to catch both the medial and lateral hamstrings. In this study, the gastrocnemius was used as a test muscle due to the ease of visualization of this muscle on ultrasonic imaging during passive exercise. However, the myofascial sequence of the lateral and medial heads of the gastrocnemius was different; [15] therefore, in this study, we performed MFR only on the lateral head of the gastrocnemius. Conversely, both the lateral and medial heads of the gastrocnemius were stretched by passive dorsiflexion of the ankle joint in the SS group. According to Kubo et al., the component of the longitudinal direction of the force exerted by the muscle fascicle determines the magnitude of the rotational moment of the joint in the pennate muscle [16]. The deep fascia of the lateral and medial heads were continuous, but MFR was only performed on the lateral head, which resulted in differences in the sliding of the deep fascia and muscle fibers. Consequently, components in the longitudinal direction may have become disproportionate and the study duration may have been insufficient to show changes in angle or strength after MFR. Temporary muscle weakness immediately after SS has already been explained through tendon spindle excitation, which is characterized by sustained elongation of the triceps surae and the suppression of muscle contraction (Ib inhibition) [17]. This is consistent with our result.

There were clear differences in fascial properties and physical function. The MFR group showed significant changes both immediately and at 4 days after the intervention compared with the SS and control groups. Nakamura et al. suggested that improving muscle flexibility by SS might improve the flexibility of connective tissue around muscle fibers instead of prolonging the length of muscle fibers [18]. Purslow also reported that connective tissue (e.g., the perimysium), was a major factor related to passive stiffness [19]. Thus, MFR might be more effective for improving fascial displacement and muscle stiffness than SS. In addition, Ichikawa et al. reported a significant increase in fascial displacement and a significant decrease in muscle stiffness immediately after MFR, [7] whereas Wong et al. reported a significant decrease in muscle stiffness [20]. Our findings support these and indicate that changes remain significant even at 4 days.

Although there were significant differences in muscle stiffness between the SS and MFR groups immediately after the intervention, there were no differences in either the angle or in fascial displacement. However, by 4 days, the MFR group tended to have a larger angle, significantly greater fascial displacement, and significantly lower muscle stiffness compared with the SS group. The mechanical properties of skeletal muscle can largely be divided into shrinkage, elasticity, viscosity, and plasticity, with muscle viscoelasticity being involved in muscle stiffness when measuring the magnitude of displacement against an external force [7]. Indeed, fascial viscosity is thought to be involved in the matrix [21]. Because the MFR group showed a significantly lower muscle stiffness, even after 4 days, we considered that MFR resolved not only the collagen and elastin fiber densification but also the matrix gelation (i.e., fascial dysfunctions) to improve viscosity. We suggest that those changes improved fascial gliding, increased fascial displacement, and increased the angle.

Concerning SS, Nakamura et al. reported a significant increase in displacement by the muscle tendon junction immediately after SS [18] and a significant decrease in muscle stiffness [22]. Akagi et al. also showed a significant acute decrease in muscle stiffness after three sets of SS for 2 minutes, with long-term effects after 5 weeks of an SS program [23,24]. However, Nordez et al. judged that there was no significant change on muscle stiffness after two sets of 2.5 minutes of SS [25]. It is possible that the SS implementation time may affect the muscle stiffness outcomes.

There are two main limitations of this study. The first relates to “stretch tolerance.” When measuring range of motion in the present study, limitation was determined subjectively based on this stretch tolerance of participants that is, to the point of pain and tolerability of the “stretchy feeling.” This has been cited as a major cause of acute changes in the range of motion assessed by SS [26,27]. However, acute changes in the range of motion and a temporary decrease in muscle strength occurred; thus, we cannot deny the possibility that changes after SS were due to a temporary change in the sense. The second limitation is that ankle joint measurements were taken in the neutral position (0°) to assess strength, fascial displacement, and muscle stiffness. According to Kawakami et al., the passive torque value of the ankle joint at 30° of plantarflexion becomes almost zero [28]. Thus, if 30° of plantarflexion indicates rest, 0° can be said to indicate that the triceps surae is extended. We do not believe that failing to measure at the original rest position of the triceps surae will have affected our results. However, it is possible that the values for strength, fascial displacement, and muscle stiffness are different in the two positions of the triceps surae.

In conclusion, we observed significant changes in fascial properties following manual MFR. These changes were consistent with improved viscoelasticity of the gelled matrix through gentle pressure and elongation, thereby eliminating collagen and elastin fiber densification. In this way, MFR restores fascial gliding during joint movement and muscle contraction. Significant changes in fascial properties remained even at 4 days after MFR, and all fascial changes were larger in the MFR group than in the SS group.

Acknowledgment

We would like to thank Enago (www.enago.jp) for the English language review.

References

  1. Takei H (2014) Myofascial release. In: Nara I, Kurosawa K, Takei H (eds.). Development of systematic treatment technique (3rdedn), Kyodo Isho publisher, Tokyo, Japan, Pg No: 13–58.
  2. Katsumata Y, Takei H, Hori T, Hayashi H (2016) Influences of muscle re-education exercises for myofascial extensibility and muscle strength after myofascial release. Rigakuryoho Kagaku 31: 99–106.
  3. Chi-Fishman G, Hicks JE, Cintas HM, Sonies BC, et al. (2004) Ultrasound imaging distinguishes between normal and weak muscle. Arch Phys Med Rehabil 85: 980–6.
  4. Maganaris CN, Baltzopoulos V, Sargeant AJ (1998) In vivo measurements of the triceps surae complex architecture in man: implications for muscle function. J Physiol 512: 603–614. [crossref]
  5. Fukunaga T, Ito M, Ichinose Y, Kuno S, et al. (1985) Tendinous movement of a human muscle during voluntary contractions determined by real-time ultrasonography. J Appl Physiol 81:1430–1433.
  6. Otsudo T, Takei H, Senoo A (2007) The influence of regulated compression for the gastrocnemius medialis muscle architectural change at rest and during isometric contraction in vivo. J Jpn Acad Health Sci (Japanese).
  7. Ichikawa K, Takei H, Usa H, Mitomo S, Ogawa D (2015) Comparative analysis of ultrasound changes in the vastus lateralis muscle following myofascial release and thermotherapy: a pilot study. J Bodyw Mov Ther 19: 327–336. [crossref]
  8. Ichikawa K, Usa H, Ogawa D, Mitomo S, et al (2013) The reliability of displacement measurement of the deep fascia using ultrasonographic imaging. J Jpn Acad Health Sci (Japanese).
  9. Murano I, Ebihara B, takihara J, Kawakami Y et al. (2016) Dynamics of the extensor retinaculum area of the Ankle measured by ultrasonography: reliability of a method for measuring the distance between the tibia and deep fascia. Rigakuryoho Kagaku.
  10. Shiina T (2014) Recent trends in research and development of ultrasound elastography. Med Imaging Technology. (Japanese).
  11. Junichi H, Mukai N, Takayanagi S, Miyakawa S (2013) The effect of muscle and tendon hardness after acute exercise: analysis on ultrasound Real-time Tissue elastography. J Phys Fit Sports Med. (Japanese)
  12. Muraki T, Ishikawa H, Morise S, Yamamoto N, Sano H, et al. (2015) Ultrasound elastography-based assessment of the elasticity of the supraspinatus muscle and tendon during muscle contraction. J Shoulder Elbow Surg 24: 120–126. [crossref]
  13. Katsumata Y, Takei H, Hayashi H, Ichikawa K (2017) Intra- and inter-rater reliabilities of measurements of fascial displacement and muscle stiffness by using ultrasound images. Rigakuryoho Kagaku. 2017 Apr 20. (Japanese).
  14. Landis JR, Koch GG (1977) The measurement of observer agreement for categorical data. Biometrics. 1977 March.
  15. Stecco L (2011) Myofascial Sequence Fascial Manipulation Theory Ed. Tokyo, Japan: Ishiyaku publisher 2011: 81–140.
  16. Kubo K, Azuma K, Kanehisa H, Kuno S, et al. (2003) Changes in muscle thickness, pennation angle and fascicle length with aging. Jap J Phys Fit Sport. (Japanese).
  17. Ninomiya I, Ando K, Kanosue K, et al. (2004) Physiology. 1st ed. Tokyo, Japan: Bunkodo 2004. (Japanese): 310–316.
  18. Nakamura M, Ikezoe T, Takeno Y, Ichihashi N. (2013) Time course of changes in passive properties of the gastrocnemius muscle-tendon unit during 5 min of static stretching. Man Ther. (Japanese).
  19. Purslow PP (1989) Strain-induced reorientation of an intramuscular connective tissue network: implications for passive muscle elasticity. J Biomech 22: 21–31. [crossref]
  20. Wong KK, Chai HM, Chen YJ, Wang CL, Shau YW, et al. (2017) Mechanical deformation of posterior thoracolumbar fascia after myofascial release in healthy men: A study of dynamic ultrasound imaging. Musculoskelet Sci Pract 27: 124–130.[crossref]
  21. Naka T (2003) A study of hyaluronic acid in skeletal muscle and its relevancy to physical therapy. Rigakuryoho. (Japanese).
  22. Nakamura M, Ikezoe T, Nishishita S, Umehara J, et al. (2017) Acute effects of static stretching on the shear elastic moduli of the medial and lateral gastrocnemius muscles in young and elderly women. Musculoskelet Sci Pract. 32:98–103.
  23. Akagi R, Takahashi H (2013) Acute effect of static stretching on hardness of the gastrocnemius muscle. Med Sci Sports Exerc 45:1348–1354.
  24. Akagi R, Takahashi H (2014) Effect of a 5-week static stretching program on hardness of the gastrocnemius muscle. Scand J Med Sci Sports 24: 950–957. [crossref]
  25. Nordez A, Gennisson JL, Casari P, Catheline S, et al. (2008) Characterization of muscle belly elastic properties during passive stretching using transient elastography. J Biomech 41: 2305–2311.
  26. Weppler CH, Magnusson SP (2010) Increasing muscle extensibility: a matter of increasing length or modifying sensation? Phys Ther 90: 438–449. [crossref]
  27. Magnusson SP, Simonsen EB, Aagaard P, Sørensen H, Kjaer M (1996) A mechanism for altered flexibility in human skeletal muscle. J Physiol 497: 291–298. [crossref]
  28. Kawakami Y, Ichinose Y, Fukunaga T (1985) Architectural and functional features of human triceps surae muscles during contraction. J Appl Physiol 85: 398–404.

Bone and Soft Tissue Tumours of the Foot and Ankle

DOI: 10.31038/IMCI.2019211

Epidemiological Considerations

Overall, tumours of the foot and ankle regions are rare. Whereas only 3 – 6 % of all osseous tumours found in the human body are confined to the pedal area, there are numbers of 5 % of all benign soft tissue tumours and at least 8 % of all malignant soft tissue tumours, resp., which are encountered in the foot and ankle [1].

Regarding pedal bone tumours, there is a strong preponderance of benign entities, reaching roughly 84 %. In contradistinction, only 50 % of all soft tissue pedal masses turn out to be benign [2].

The frequency (excluding ganglion cysts) of occurence of pedal tumours is divided into two peaks: the first peak falls into the first decade of life whereas the the second (smaller) peak lies within the 8th decade [3]. There is no overt difference in sex and race.

Local Distribution of Pedal Tumours

Considering bony tumours of the foot and ankle, the vast majority of these tumours are arising in the hindfoot and ankle, resp. Metatarsal bones as well as phalangeal bones are much less frequently affected. This is quite different in comparison to soft tissue tumours where the forefoot is the foremost afflicted site of such tumours [1].

Signs and Symptoms of Pedal Tumours

One major problem in identifying pedal tumours is confined to the fact that foot pain is a common feature due to daily mechanical stress, which can masquerade tumour-induced pain. Another problem is given by the fact that pedal tumours are often outside of a physician´s scope because of their rarity and are therefore not taken into account.

Although „lumps and bumps“ are readily detected by clinical investigation due to shallow soft tissue layers, covering the foot, diagnosis is nevertheless considerably delayed (2- to 3-fold compared to other body regions) [4]. This delay in establishing a timely diagnosis has usually to do with an underestimating these tumours as they are appearing as small masses. Small, well-demarcated and rounded soft tissue masses are erroneously considered as being simply benign or harmless, resp [5]. As a consequence, this assumption may lead to misdiagnosis and treatment failure. Fortunately, both delayed diagnosis and treatment do not deteriorate prognosis and overall survival because of the very slow pedal tumour growth rate (10 – 20-fold reduced growth rate compared to the rest of the body) and the overall small tumour size [6].

Special Anatomical Situation of the Foot and Ankle

Compartimental anatomy of foot and ankle is quite different compared to other body regions. Whereas the plantar soft tissue of the foot can be divided into distinct compartments, the dorsal aspect of the foot is mainly unseparated and therefore considered extra-compartimental. The same applies to the ankle region which is also considered extra-compartimental due to thin and perforated septae, allowing free tumour spreading. Furthermore, close relationship of some tumours to plantar neurovascular bundles may cause severe functional deficits in the case of foot-sparing resective procedures. Proper knowledge of unique compartmental anatomy is therefore of particular importance for surgical plannings [7].

Tumours smaller than 3 cm should be subject to excision biopsies if safely possible. Tumours larger than 3 cm should be diagnosed by open excision biopsy or by percutaneous core biopsy, using closed coaxial biopsy systems alternatively. No matter which biopsy strategy comes into operation, compartmental anatomy has to be respected otherwise the entire extremity is threatened to be lost due to compartimental contamination.

Imaging Diagnostic Work-Up

Plain Radiography: X-ray examination should be the first imaging modality if a mass lesion of the foot is present because of at least three reasons: 1, to get an overview about the osseous situation of the entire pedal skeleton; 2, to localize and characterize bony lesions if present; 3, to detect calcifications or ossifications within the mass lesion (the so-called tumour matrix).

Ultrasonography: Ultrasound examination plays an important role in the work-up of any palpable mass lesion in the foot. Because ganglion cysts are frequently encountered in the ankle and forefoot areas, ultrasonography is capable to clearly identify pure cystic lesions, thus they can be excluded from further clearing. If there are cyst-like lesions which are not clearly referred to as pure cysts or if there are solid soft tissue masses present, they all should be further evaluated, using MRI.

Computed Tomography: CT comes into play in such cases where bony abnormalities or osseous tumours, resp., should be further evaluated. CT proves to be helpful with the pedal skeleton because of its complex anatomy to image all bony components without superposition. Furthermore, CT is most sensitive if (even subtle) calcifications are looked for. Evidence of soft tissue calcificatons or ossifications, resp., turns out to be of paramount importance for differential diagnostic considerations (e.g., crystal depositions, phleboliths, ossifying myositis, chondrogenic calcifications, calcifications in synovial cell sarcoma).

Magnetic Resonance Imaging: MRI is the most powerful diagnostic modality within the diagnostic approach to pedal tumours. Superior soft tissue contrast helps to delineate and to differentiate both soft tissue masses and bone tumours, particularely for staging purposes (Enneking staging system, AJCC staging system). Contrast-enhanced techniques are able to distinguish viable and cystic or necrotic areas within the masses which is in particular helpful as a guidance for biopsy or resection plannings, resp.

Other Imaging Modalities: such as nuclear medicine techniques (bone scintigraphy, positron-emission-tomography) and digital subtraction angiography are all of minor importance in the routine diagnostic work-up of pedal tumours.

Tumours and Tumour-Like Lesions of the Foot and Ankle

In general, commonly encountered bone and soft tissue tumours of the human body can all be found in the foot and ankle, too. However, there are some special issues with such pedal tumours.

The majority of pedal osseous tumours are benign, comprising osteomas, osteochondromas, osteoid osteomas, as well as osteoblastomas, chondroblastomas, and enchondromas. Furthermore, there are also lytic bony lesions, including cysts (e.g., intraosseous ganglia, geodes, ABC), and giant cell tumours. There is a peculiar trabecular-poor area within the calcaneal body (stress-shielded region) which often develops intraosseous lipomas (vicarious lipoma). Those lipomas in turn may render liquid or they become calcified due to fat cell necrosis [8].

Malignant bone tumours of the foot are – as said earlier – very rare and constitutes of osteo- and chondrosarcomas as well as Ewing sarcomas. Although they are rare, they carry the same potential of both local recurrence and metastastic spreading as similar tumours somewhere else in the human body [9].

Considering soft tissue tumours, the pedal situation is somewhat different: cysts, ganglia, and bursae are frequently encountered because of the excusively joint- and tendon-rich anatomcial conditions alongside the entire foot and ankle. Leaving them out, there are a lot of benign solid tumours which are found in the foot: plantar fibromatosis, tenosynovial giant cell tumour, lipoma, neurogenic tumours, as well as hemangiomas and vascular malformations. In the forefoot, there is an unique tumour-mimicking entity, the so-called Morton´s neuroma. Being actually a misnomer, Morton´s neuroma is not a true neoplasia but rather a perineural reactive fibrosis. In contradistinction, to pedal bony tumours, there is a significant number of malignant soft tissue tumours, comprising synovial cell sarcoma, clear cell sarcoma, and epitheloid sarcoma [10]. While rarely encountered elsewhere in the human body, these malignant tumours are relatively typical for pedal soft tissue malignancies. Moreover, some of these soft tissue sarcomas are able to metastasize, using lymphatic pathways.

Although soft tissue sarcomas of the foot are – in general – less aggressive when compared to other body regions, the risk of local tumour recurrence is high because of the unique compartimental situation at the foot and ankle. For this reason, expectative procedural approach in the case of potentially malignant pedal tumours is highly questionable and amputations remain a mainstay in the curative therapy of these tumours [11].

References

  1. Chou LB, Ho YY, Malaver MM (2015) Tumours of the foot and ankle: experience with 153 cases. Foot Ankle Int 30: 836–841.
  2. Ruggieri P, Angelini A, Jorge FD, Maraldi FD, Gianinni S (2014) Review of foot tumors seen in a university tumor institute. J Foot Ankle Surg 53: 282–285.
  3. Yang P, Evans S, Bali N, Ramsamy A, Evans R (2017) Malignant bone tumours of the foot. Ann R Coll Surg Engl 99: 566–572.
  4. Brotzmann M, Hefti F, Baumhoer D, Krieg AH (2013) Do malignant bone tumors of the foot have a different biological behavior than sarcomas at other skeletal sites? Sarcoma 2013:767960.
  5. Toepfer A (2017) Tumors of the foot and ankle – a review of the principles of diagnostics and treatment. Fuß Sprunggelenk 15: 82–96.
  6. Walter JH, Goss LR (2017) How to detect soft tissue tumors. Podiatry Today 16: 82–96.
  7. Erickson SJ, Rosengarten JL (1993) MR imaging of the forefoot: normal anatomic findings. AJR Am J Roentgenol 160: 565–571.
  8. Malghem J, Lecouvet F, Vande Berg BC (2017) Calcaneal cysts and lipomas: a common pathogenesis? Skeletal Radiol 46: 1635–1642.
  9. Mascard E, Gaspar N, Brugières L, Glorion C, Pannier S, et al (2017) Malignant tumours of the foot and ankle. EFFORT Open Rev  2: 261–271.
  10. Woertler K (2005) Soft tissue masses in the foot and ankle: characteristics on MR imaging. Semin Musculoskelet Radiol 9: 227–242.
  11. Marqués B, Terrier P, Voigt JJ, Mihura J, Coindre JM (2000) Clear cell soft tissue sarcoma. Clinical, histopathological and prognostic study of 36 cases. Ann Pathol 20: 298–303.

Reimbursement Challenges in Europe for Innovative Therapies

DOI: 10.31038/JPPR.2019221

 

The thinking about the role of health care systems has been evolving over the last ten years such that there is more recognition of the importance of healthy populations on overall wealth and security [1].  At the European level and in WHO studies have shown that the positive return on investment in health systems is between 50% and 250% [2].  At the same time with the exploding advances in understanding how the body works, innovative therapies are proliferating at an ever so rapid pace [3].  What these innovations have in common that was not the case in the past is that they are more focused.  Their patient populations are smaller. They are more efficient.  That is to say those innovations a generation ago were targeting large populations (Block Buster drugs) with diseases for which we had a significant understanding at that time.  Today as scientific understanding is digging deeper into the chemistry of the body, the challenges for health care systems have focused on the rising costs and limited budgets.

The responsibility at the European level is to make sure that new therapies are safe.  Unlike in the US where the FDA is responsible for safety, they are also in some cases, responsible for reimbursement.  In Europe, there is a clear distinction between these roles.  Reimbursement is a Member State responsibility.  To talk about reimbursement challenges immediately devolves into 27 different health care systems.  So what commonalities can be used to address the way Reimbursement Authorities are taking on these challenges without becoming too bogged down into individual health care systems?  This article will assess the strategies for pricing, early access, budget controls and cost-effectiveness.

Pricing

While there is a range of approaches to pricing from initially allowing free pricing as in Germany, governmental negotiation on pricing as in France, prices pegged to categories of medications as in Spain to prices determined by cost-effective algorithms as in the UK.  The challenges facing Reimbursement Authorities are to identify a ‘fair’ price, given the pharmaceutical industry’s investment in creating innovative therapies.  Any meaningful discussion of the impact on pricing of access to medications or the overall health of the population is complicated by the fact that within each Member State, pricing policies are specific to where the treatment is provided (inpatient, outpatient, etc.) and often by region.  Nevertheless, there is no evidence that one strategy leads to better health than another strategy.  While prices do vary by country, going back to the initial premise that access to innovative treatment has a positive effect on society; it is not yet clear to what extent the price level contributes or takes away from overall societal wellbeing.  That is, when does the price get so high that the benefit is not justified?

Early Access

Early access programs are available throughout Europe but the intent and foci vary greatly.  The rationale for these programs is to assure that patients receive treatments that are specifically life-saving during the Regulatory (EMA level) and Reimbursement (Member State level) processes that can take from months to years.  The criteria and payment for these programs range from fully funded small populations with exceptional circumstances such as in Italy to broader patient groups in France and only partially funded or not funded as in the UK [4].  Some programs become available as soon as the new drug is being reviewed at the European level whereas others wait until approval is given but the Member State has yet to finish its deliberative process.  Some of the key considerations of manufacturers are how the program may effect pricing and what additional safety studies may be required.  There is general acceptance that these programs do provide a needed bridge that allows access to innovation that would not have been possible without their existence.

Budget Controls

Given the conflicting forces of improved health benefits and rising costs, the mechanism Member States are focusing on are ways to manage their budgets.  One of the limitations with this effort is that budgets are divided into categories that are self-contained.  That is, the health care budget is reviewed and those in charge are responsible irrespective of other budgets.  Hence, positive results from expenditures in health are not monetised and applied to non-health budgets.  Worse yet, within the health system, the various budgets are also independent.  A classic example is when an innovative medication results in patients avoiding hospitalisations.  The drug budget goes up and the hospital budget goes down in reality but is not captured in a meaningful way.

Strategies to account for cross-budget effects are beginning to emerge.  One important improvement has been in the move in all Member States to capitated hospital budgets.  There are various names for this but they are adaptations of the Diagnostic Related Grouping that was adopted in the US for Medicare hospital payments in the 1980s.  At least in hospitals, the medication costs are not independently budgeted.  If an innovation results in a shorter length of hospital stay, the hospital is able to benefit in the short run.

Non-hospital budget control strategies have been focused on pharmacy constraints such as requiring generic substitution.  Depending on the details of the policy, this could impact the willingness of manufacturers of innovative medications to offer access.

As yet, no budgetary control system has been able to integrate the budget impact of improved health from innovative therapies on the wealth and economic success of the country.

Cost-effectiveness

Another strategy for improved reimbursement decisions has been the advent of economic algorithms that try to capture the costs and benefit at the same time to arrive at a single ratio to be used in decision making.  There is strong conceptual support for this in economic theory. This was introduced over 20 years ago in the UK and has been adapted in several other Member States.  The concept is to compare the costs to a common health outcome.  Since health outcomes are not common, the most widely used created outcome is the Adjusted Life Years Saved.  This ratio simplifies comparisons across disparate therapies.  Without going into the mechanics of this approach, this approach presents the following issues for innovative therapies.

First is the pragmatic access to all costs over the lifetime of the public (patients, families, workplaces, etc.) affected by the therapy.  While direct therapeutic costs are often in claims processing databases, other costs are not.  Next is the significant shortfall in measuring the elements of the outcomes.  Without going into the extensive literature on these current shortfalls, there has been an emerging area of research in Real World Data to address some of these concerns.  This field is in its infancy but the future may lead to improved measurement of health outcomes.  Finally and potentially more importantly is the question of:  ‘What is a sufficient ratio to allow reimbursement of the innovation?’  Here, economic theory cannot help.  There is no yardstick to determine acceptability.  The UK has set ratios between 20k£ and 30k£ but there is no scientific support for this.  Worse yet, the ratios generated for innovative therapies for small populations fall far outside of this yardstick leading countries using economic algorithms as decision making guidelines to rethink their usefulness.

Conclusion

Hopefully innovative therapies will continue to proliferate and the health and economic security of the public will benefit from them.  At the same time, reimbursement policies need to evolve the take into consideration the new reality of the marvellous new world we are living in.

References

  1. McKee L, Suhrcke M, Nolte E, Lessof S, Figueras J, et al (2009) Health systems, health, and wealth : a European perspective. The Lancet 373 : 349–351.
  2. Suhrcke M, Rocco L, McKee M (2007) Health : a vital investment for economic development in eastern Europe and central Asia. Copenhagen : WHO Regional Office for Europe on behalf of the European Observatory on Health systems and Policies, 2007.
  3. Godman B, Bucsics A, Vella Bonanno P, Oortwijn W, Rothe C, et al (2018) Barriers for access to new medicines : Searching for the balance between rising costs and limited budgets. Fronties in Public Health 328.
  4. Urbinati D, Masetti L, Toumi M (2012) Early Access Programmes (EAPs) : Review of European system, ISPOR 15th Annual European Congress, Berlin, Germany.

The Positive Effect of Skd Plus Iot and Hbo2t In The Treatment Of Cancer [Introducing Sorush Cancer Treatment Protocol (Sctp)]

DOI: 10.31038/CST.2019414

Abstract

Background: The aim of this research is to figure out the effectiveness of the Sorush Cancer Treatment Protocol (SCTP) which is based on the Evolutionary Metabolic Hypothesis of Cancer (EMHC) and introducing the Specific Ketogenic Diet (SKD) plus Intravenous Ozone Therapy (IOT) in Phase (1) on 54 cancer patients, and combination of Hyperbaric Oxygen Therapy with vitamin/mineral and herbal supplementation beside the SKD and IOT in Phase (2) of this research on the remaining 31 cancer patients.

Introduction: Cancer based on the introduction of EMHC by Dr. Somayeh Zaminpira and Dr. Sorush Niknamian in 2017, is an evolutionary metabolic disease and through the incline of the Reactive Oxygen Species (ROS) and the Butterfly Effect in normal eukaryotic cells, the mitochondria become damaged or shut down. Cancer cells are primitive eukaryotic cells which have existed since around 1.5 billion years ago before the entrance of mitochondrion as endosymbiont.

Materials and Methods: Based on the researches from 1928–2016 and the experimentation of cancer treatments and protocols on cancer patients, we have reached a treatment and decided to test it on 54 voluntary cancer patients in the first stage of their disease. In this treatment we used a 5-day water fasting state, the Specific Ketogenic Diet (SKD) designed by ourselves and Intravenous Ozone Therapy (IOT) in the duration of 90 days (Phase 1) and another 90 days (Phase 2) with the entrance of Hyperbaric Oxygen Therapy (HBO2T) and several supplements which  have been effective in previous studies on cancer patients. We have used the measurement of saliva PH, the MRI device and statistical methods to test the shrinkage of the tumors.

Results: After Phase (1) of this research on 54 patients the average percentage decrease in the tumors was 58% and after Phase (2) on 31 remaining cancer patients the average percentage decrease in the tumors was 98.8%. The average saliva PH in the fasting state of the cancer patients improved from acidic to alkaline as well.

Conclusion:in conclusion, we have reached an effective cancer treatment based on SCTP by the usage of SKD, IOT, HBO2T and several supplements. There was an obvious improvement of cancer tumor decrease, lifestyle, saliva PH and we did not observe any side effects or cachexia in any of the patients.

Keywords

EMHC Hypothesis, SKD, IOT, ROS, HBO2T, SCTP

Introduction

Evolutionary Metabolic Hypothesis of Cancer (EMHC)

The first living cells on Earth are thought to have arisen more than 3.5 × 109 years ago, when the Earth was not more than about 109 years old. The environment lacked oxygen but was presumably rich in geochemically produced organic molecules, and some of the earliest metabolic pathways for producing ATP may have resembled present-day forms of fermentation. In the process of fermentation, ATP is made by a phosphorylation event that harnesses the energy released when a hydrogen-rich organic molecule, such as glucose, is partly oxidized. The electrons lost from the oxidized organic molecules are transferred via NADH or NADPH to a different organic molecule or to a different part of the same molecule, which thereby becomes more reduced. At the end of the fermentation process, one or more of the organic molecules produced are excreted into the medium as metabolic waste products. Others, such as pyruvate, are retained by the cell for biosynthesis. The excreted end-products are different in different organisms, but they tend to be organic acids. Among the most important of such products in bacterial cells are lactic acid which also accumulates in anaerobic mammalian glycolysis, and formic, acetic, propionic, butyric, and succinic acids [1]. The first cell on the earth before the entrance of the bacteria did contain  a nucleus and used the fermentation process to produce ATP for its energy. Then an aerobic proteo-bacterium enters the eukaryote either as a prey or a parasite and manages to avoid digestion. It then became an endosymbiont. As we observe, the fermentation process used the glucose or even glutamine to produce ATP, but the aerobic process used the glucose, fat and protein to produce more ATP than the previous one. The symbio-genesis of the mitochondria is based on the natural selection of Charles Darwin. Based on Otto Warburg Hypothesis, in nearly all cancer cells, the mitochondrion is shut down or is defective and the cancer cell does not use its mitochondria to produce ATP [2]. This process of adaptation is based on Lamarckian Hypothesis of Evolution and the normal cells goes back to the most primitive time of evolution to protect itself from apoptosis and uses the fermentation process like the first living cells 1.5 billion years ago.  Therefore, cancer is an evolutionary metabolic disease which uses glucose as the main food to produce ATP and Lactic Acid. The prime cause of cancer is the abundance of Reactive Oxygen Species produced by mitochondria that is a threat to the living normal cell and causes mitochondrial damage mainly in its cristae [3].

Specific Ketogenic Diet (SKD)

Ketogenic diet is a kind of regime which uses high fat content and low carbohydrate. This diet changes the metabolic state into the condition called Ketosis. After several days, fat becomes your body’s primary energy source which causes an increase in the levels of compounds which are called “ketones” in the blood [4]. In general, a ketogenic diet used for weight loss is about 60–75% of calories as fat, with 15–30% of calories from protein and 5–10% of calories from carbs. However, when a ketogenic diet is being used therapeutically for the treatment of cancer, the fat content may be significantly higher that is up to 90% of calories, and the protein content lower [5]. The SKD contains 80% saturated fat, 15% protein with the lowest Glutamine content and 5% high-fiber carbohydrates mainly in the form of cruciferous vegetables.

Materials and Methods

Based on the researches from 1928–2016 and the experimentation of cancer treatments and protocols on cancer patients, we have reached a treatment and decided to test it on 54 voluntaries cancer patients. In this treatment we used a 5-day water fasting state to put the cancer patients body on cannibalism state. In this period of the experiment, normal body cells digest abnormal cancerous cells for food. Thomas N. Seyfried et al, 2012 After the water fasting period, we began the Specific Ketogenic Diet (SKD) designed by ourselves and Intravenous Ozone Therapy (IOT) in the duration of 90 days (Phase 1) and another 90 days (Phase 2) with the entrance of Hyperbaric Oxygen Therapy (HBO2T) and several supplements which have been effective in previous studies on cancer patients. We have also used the measurement of the saliva pH in the fasting state, the MRI device and statistical methods to test the decrease in size of the tumors. The dosage of the intravenous ozone therapy (IOT) which we used was: 42ug/cc on the first month, 56 ug/cc on the second month and 70ug/cc on the third month in the Phase (1) and 70ug/cc once per week and HBO2T twice per week in the Phase (2) of our research. This type of IOT was due to a decrease in the allergic reaction by the patients. Entering the vitamin/mineral, herbal supplements and probiotic foods benefited cancer patients in their mood and decreased the possibilities of depression and anxiety.

PHASE (1)

In Phase (1) of our research, there were two sessions of IOT on Saturdays and Tuesdays. There was no supplementation in this Phase of our experiment. The SKD is a type of Ketogenic Diet which consists of 80% saturated fat (Organic Cow Butter, Organic Cow Tallow and Coconut oil), 15% protein with lowest Glutamine content (Fish meat, shrimp, organic calf meat, organic whole eggs, organic chicken and low glutamine protein powder.) and 5% complex-high fiber carbohydrate (whole vegetables, cruciferous vegetables, lettuce, white mushrooms and dark green fruits). The consumption of any dairy, artificial sweeteners as well as stevia, vegetable oils, margarines, pig’s meat, soy products, sugar, alcohol, gluten and fruit juices were prohibited in this research. The Total calorie intake of this Diet should be 1200–1500 Cal/Day. The patients used fermented foods (Kimchee, Miso or Natto) every day for their benefits as probiotics to improve their digestion and absorbing important vitamins/minerals. For the improvement of the patients’ body pH and absorbing some important minerals, they have been given vegetable juice twice per day (500 ml/day). The intravenous ozone therapy (IOT) which we used was: 42ug/cc on the first month, 56 ug/cc on the second month and 70ug/cc on the third month. This type of IOT was done to decrease the allergic reaction by the patients. There was not any record of allergic reactions or side effects after the Phase (1) of the study.

The measurements and statistical data are as below:

Table (1) shows the number of patients, gender and the range of their age. As we can see, the highest number cancer types belong to the breast cancer and the lowest belongs to the kidney, colorectal, and lung cancer.

Table 1

Number

Cancer Types

Number of Patients

Male

Female

Range of Age

1

Brain Cancer

11

7

4

35–75

2

Breast Cancer

18

0

18

25–75

3

Colorectal Cancer

5

1

4

42–67

4

Kidney Cancer

5

3

2

25–60

5

Liver Cancer

10

8

2

35–64

6

Lung Cancer

5

4

1

40–70

As we can observe in the Table (2), the saliva pH of the cancer patients has improved by the SKD and IOT.

Table 2

Cancer Types

Saliva pH Range Before Treatment

Saliva pH Range After Phase (1) of the Treatment

Brain Cancer

6.5–6.9

7.0–7.6

Breast Cancer

6.8–7.1

7.0–7.3

Colorectal Cancer

6.0–6.2

7.0–7.2

Kidney Cancer

6.3–6.5

7.0–7.4

Liver Cancer

6.7–6.9

7.1–7.5

Lung Cancer

6.3–6.7

7.1–7.3

Table (3) and Figure (1) shows that the tumor size average of the cancer patients is decreased by 58% after 90 days of the controlled trial.

Table 3

Cancer Types

Tumor Size Before Treatment in Millimeter

Tumor Size Average in Millimeter

Tumor Size Average After Phase (1)
In Millimeter

Brain Cancer

5.00–29.00

17.00

2.21

Breast Cancer

5.00–30.00

16.50

4.12

Colorectal Cancer

5.00–7.00

6.00

4.50

Kidney Cancer

7.00–9.00

8.00

3.68

Liver Cancer

10.00–26.00

18.00

11.16

Lung Cancer

7.00–22.00

14.50

8.00

CST Article_ Sorush Niknamian_F1

Figure 1. Blue line shows the average size of the tumors before the experiment begins and the orange line shows the tumor size of the patients after 90 days.

PHASE (2)

After Phase (1) of this research which took 90 days, 23 of the patients  left the experiment due to passing away because of old age, car accident or not having enough hope for the future treatment. Some of them wanted to live with their families or saying goodbye to them and some of them did not do exactly the diet so we decided not to continue the treatment on them.  We continued the treatment on the remaining 31 patients for the next 90 days. After Phase (1) of our study, we did not observe any cachexia in the patients.

The Phase (2) of the research is the same as the Phase (1) in the Diet and Intravenous Ozone Therapy (IOT). We decided to enter Hyperbaric Oxygen Therapy (HBO2T) and special supplementation including vitamins/minerals and some herbal supplementation in our treamtent. There was one session of IOT on Saturdays with 70 ug/cc, and two sessions HBO2T which took 60 minutes in Mondays and Wednsedays. We did not have any HBO2T chamber so we decided to give the patients the pure oxygen inhalation by the oxygen container for 60 minutes every session.

(Table 4, 5, 6) (Figure 2)

Table 4

Number

Cancer Types

Number of Patients

Male

Female

Range of Age

1

Brain Cancer

7

5

2

35–75

2

Breast Cancer

14

0

14

25–75

3

Colorectal Cancer

1

0

1

45

4

Kidney Cancer

2

1

1

50–62

5

Liver Cancer

5

4

1

35–64

6

Lung Cancer

2

2

0

40–47

Table 5

Cancer Types

Saliva pH Range After Phase (1)

Saliva pH Range After Phase (2)

Brain Cancer

7.0–7.6

7.2–7.5

Breast Cancer

7.0–7.3

7.1–7.3

Colorectal Cancer

7.0–7.2

7.1–7.2

Kidney Cancer

7.0–7.4

7.1–7.5

Liver Cancer

7.1–7.5

7.2–7.4

Lung Cancer

7.1–7.3

7.2–7.3

Table 6

Cancer Types

Tumor Size Average in Millimeter

Tumor Size Average After Phase (1) in Millimeter

Tumor Size Average After Phase (2) in Millimeter

Brain Cancer

17.00

2.21

0.00

Breast Cancer

16.50

4.12

0.00

Colorectal Cancer

6.00

4.50

0.21

Kidney Cancer

8.00

3.68

0.00

Liver Cancer

18.00

11.16

0.00

Lung Cancer

14.50

8.00

0.14

CST Article_ Sorush Niknamian_F2

Figure 2. The blue line shows the tumor size before the experiment begins. The orange line shows the tumor size after Phase (1) of the treatment. The white line shows the shrinkage and improvement of the cancer patients tumors after 180 days.

As we can see in Table (5), the saliva pH of the patients is improved from acidic into the alkaline.

Table (6) and Figure (2) show the improvement of the tumor sizes from the beginning of the research, after Phase (1) and after Phase (2). After 180 days of this experiment, we have copmpeletly shrunk the tumor in 4 types of cancer patients and the remaining two have had the tumor size profoundly reduced.

Although we tried to find the natural vitamin/mineral supplement, the only one was “Immunace” by “vitabiotics company”, which had the near dosage we wanted to give to the patients. They were given one tablet of this supplement every night with dinner. They were given 3000 mg of Ascorbic acid (500 mg every two hours), one cup of cottage cheese with 5 gr of flaxseed oil every night for dinner (Table 7).

Table 7. Specific doses for supplements given to the patients.

Daily advantage herbal

Daily dose suggested in SCTP

Chlorella Vulgaris

8000 mg (Early in the morning in the fasting state with water)

Turmeric

500 mg (Three times per day with meal)

L-Taurine

400 mg

Bee Pollen

5000 mg  mixed with the low glutamine protein powder

Acetyl-L-Carnitine

2000 mg/day

Green tea extract

500 mg 30 minutes before lunch

Panax Gingeng

100 mg with breakfast

Alpha Lipoic Acid (ALA)

300 mg/Day

Results

This research was a controlled study on 54 cancer patients of several kind of cancers. We have put the study in two phases. Each phase took 90 days with different number of patients. In the Phase (1) there were 54 patients with 6 types of cancer: Brain cancer, Breast cancer, Colorectal Cancer, Kidney Cancer, Liver cancer and Lung cancer. We measured their saliva pH before the therapy in the fasting state which were totally acidic. We began the 5-day water fasting, SKD (with 1200–1500 Cal/Day) and IOT on the patients with no supplementation added. After 90 days we observed the tumor shrinkage obviously in all the patients as we can see in Table 3, and improvement in saliva pH from acidic into alkalinity in 90% of the patients.

In the Phase (2) of the study, the number of patients was reduced to 31 and we introduced supplemental vitamin/minerals, HBO2T and Herbal Supplements. The IOT reduced from two sessions to one session per week and HBO2T to two sessions per week to saturate the cancer cells with more oxygen and increasing the amounts of ROS in cancer cells. After Phase (2) which took another 90 days, the saliva PH of all patients became alkaline and several tumors disappeared completely: Brain cancer, Breast cancer, Kidney cancer and Liver.

In two types of cancer the tumor did not disappear completely but the tumors shrinkage improved obviously to less than 0.3 mm which was a marvelous result: Colorectal cancer and Lung cancer. The total survival of the patients was 99.7% and the improvement in the saliva pH was 100% in this research which shows the effectiveness of this methodology of cancer treatment.

Discussion

The effective diet introduced in this research is the Specific Ketogenic Diet (SKD) programmed by Dr. Somayeh Zaminpira and Dr. Sorush Niknamian. Normal cells use the sophisticated process of respiration to efficiently turn any kind of nutrient that is fat, carbohydrate or protein into high amounts of energy in the form of ATP. This process requires oxygen and breaks food down completely into harmless carbon dioxide and water. Cancer cells use a primitive process of fermentation to inefficiently turn either glucose from carbohydrates or the amino acid glutamine from protein into small quantities of energy in the form of ATP. This process does not require oxygen, and only partially breaks down food molecules into lactic acid and ammonia, which are toxic waste products. The most important result is that fatty acids or more generally, fats cannot be fermented by cells [6]. (Figure 3) shows the basic nutrition contents in the SKD.

CST Article_ Sorush Niknamian_F3

Figure 3. The Specific Ketogenic Diet (SKD).

The reason behind this kind of diet for cancer patients is to starve cancer cells and make them weak. Most patients cannot use cancer ketogenic diets due to gastrointestinal discomfort or high amount of fat which is 90%. SKD uses 80% fat in the form of saturated animal and coconut oil which are less likely to cause adverse side effects such as diarrhea.  Food restriction reduces the incidence of both inherited and acquired cancers in laboratory animals [7]. Most cancer cells grow best when they have access to a combination of glucose and the amino acid glutamine. But, there are some types of cancer cells which do just fine without any glucose as a food source, because they are especially good at burning glutamine. This is why both glucose from dietary carbohydrates and glutamine from dietary protein, need to be restricted in order to best target cancer cells. Therefore, a low-calorie ketogenic diet consisting of 90% fat, with the rest 10% being made up of protein plus carbohydrate maybe the best way to starve cancer cells. This diet forces normal cells to burn fat for energy. It contains enough protein for normal cells to function properly. Excess protein means excess amino acids and glutamine. The ketogenic diet does not have to contain any carbohydrate, However, it is not harmful if  it contains significant amounts of carbohydrate, as long as calories are kept low. Blood glucose levels respond more to calorie intake than to carbohydrate intake [8]. This is the reason for the lowest glutamine intake in the SKD (Figure 4).

CST Article_ Sorush Niknamian_F4

Figure 4. Explanation of different Ketogenic Diets [9].

Ozone has been found to be an extremely safe medical therapy, free from side effects. In a 1980 study done by the German medical society for ozone therapy, 644 therapists were polled regarding their 384,775 patients, comprising a total of 5,979,238 ozone treatments administered. There were only 40 cases of side effects noted out of this number which represents the incredibly low rate of 0.000007% and only 4 fatalities. Ozone has thus proven to be the safest medical therapy ever devised [10]. Ozone therapy causes an increase in the red blood cell glycolysis rate. This leads to the stimulation of 2,3-diphosphoglycerate which leads to an increase in the amount of oxygen released to the tissues. Ozone activates the Krebs cycle by enhancing oxidative carboxylation of pyruvate, stimulating production of ATP. It also causes a significant reduction in NADH and helps to oxidize cytochrome C. There is a stimulation of production of enzymes which act as free radical scavengers and cell-wall protectors: glutathione peroxidase, catalase and superoxide dismutase. Production of prostacyline, a vasodilator, is also induced by O3 [11].

Ozone administered at a concentration of between 30 and 55 μg/cc causes the greatest increase in the production of interferon and the greatest output of tumor necrosis factor and interleukin-2. The production of interleukin-2 launches an entire cascade of subsequent immunological reactions. [11] Ozone exposure induces a significant mean decrement in vital capacity. It significantly increases mean airway resistance and specific airway resistance but does not change dynamic or static pulmonary compliance or viscous or elastic work. It also significantly reduces maximal transpulmonary pressure. And further more significantly increases respiratory rate and decreases tidal volume [12–20].

There were no side effects like allergic reactions and gastrointestinal discomfort of this methodology of treatment recorded in this research and it was safe. HBO2T in combination with IOT and SKD reduced the acidity and pain in the patients as well.

We name this methodology used in this treatment the Sorush Cancer Treatment Protocol (SCTP). This protocol includes: 5-day water fasting, SKD, IOT, HBO2T, natural Vitamin/Mineral Supplements, Herbal Supplements, 3000–5000 mg ascorbic acid, probiotic foods and cottage cheese mixed with flaxseed oil. The total calorie intake by the patients should be 1200–1500 Cal/Day. The dietary restrictions in this protocol are: Dairy, Industrial Vegetable oils, Margarines, Alcohol, Gluten, Soy Products (Miso and Natto are exceptional), Artificial Sweeteners as well as Stevia, Fruit juices and any types of sugar including Honey.  The duration of the SCTP should not exceed 6 months to reduce the possibilities of ketoacidosis occurrence in patients.

Acknowledgement

This research is sponsored by the Violet Cancer Institute (VCI) and Weston A. Price Foundation (WAPF).

Conclusion

Using the Specific Ketogenic Diet (SKD) in combination with the Intravenous Ozone Therapy (IOT) resulted in the shrinkage in 6 cancer tumor types (Brain Cancer, Breast Cancer, Colorectal Cancer, Kidney Cancer, Liver Cancer and Lung Cancer) in vivo and improved the fasted saliva pH of the patients from acidic into alkaline after 90 days. By introducing the supplements including Vitamin/Mineral, Herbal supplements shown in (Table 7), Ascorbic Acid mega dosage (3000 mg/day) and Hyperbaric Oxygen Therapy (HBO2T) into our research, all the patients went into complete remission except colorectal and lung cancer in 180 days. The tumors of the remaining cancer patients decreased to less than 0.3 mm in size which shows the effectiveness of this cancer treatment protocol. There were no records of side effects including gastrointestinal discomfort and cachexia in this experiment. The pain related to the type of tumors in patients improved, the saliva pH of all patients became alkaline and the lifestyle of all patients improved after 180 day of the treatment. that the diet needs to be organic and that foods of the highest quality should be chosen. We suggest not using the SKD for more than 6 months to reduce the possibility of ketoacidosis in patients (Figure 5).

CST Article_ Sorush Niknamian_F5

Figure 5. SCTP procedure in brief.

List of Abbreviations:

EMHC: Evolutionary Metabolic Hypothesis of Cancer

SKD: Specific Ketogenic Diet

IOT: Intravenous Ozone Therapy

ROS: Reactive Oxygen Species

HBO2T: Hyperbaric Oxygen Therapy

SCTP: Sorush Cancer Treatment Protocol

References

  1. The Evolution of Electron-Transport Chains, Molecular Biology of the Cell. 4th edition. 2002, Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983, 1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson. Bookshelf ID: NBK26849.
  2. Keeling PJ, Archibald JM (2008) Organelle evolution: what’s in a name? Curr Biol 18: 345–347. [crossref]
  3. WARBURG O (1956) On the origin of cancer cells. Science 123: 309–314. [crossref]
  4. Volek JS, Fernandez ML, Feinman RD, Phinney SD (2008) Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome. Prog Lipid Res 47: 307–318. [crossref]
  5. Allen BG, Bhatia SK, Anderson CM, EichenbergerGilmore JM, Sibenaller ZA, et al. (2014) Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol 2: 963–970.
  6. Soroush Niknamian (2016) The Prime Cause, Prevention and Treatment of Cancer, International Science and Investigation Journal, ISSN: 2251–8576, 5(5), Journal homepage: www.isijournal.info.
  7. Valter D Longo, Luigi Fontana (2010) Calorie restriction and cancer prevention: metabolic and molecular mechanisms, Trends Pharmacol Sci. Author manuscript; available in PMC 2011 Feb 1. Published in final edited form as: Trends Pharmacol Sci 31: 89–98.
  8. Chevrollier A, Loiseau D, Gautier F, Malthièry Y, Stepien G (2005) ANT2 expression under hypoxic conditions produces opposite cell-cycle behavior in 143B and HepG2 cancer cells. Mol Carcinog 42: 1–8. [crossref]
  9. Allen BG, Bhatia SK, Anderson CM, EichenbergerGilmore JM, Sibenaller ZA, et al. (2014) Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol 2: 963–970.
  10. Somayeh Zaminpira, Sorush Niknamian, LAP LAMBERT PUBLICATION GROUP, 2017, [ISBN: 978-620-2-05082-1]
  11. Washutti J, Viebahn R, Steiner I (1990) The influence of ozone on tumor tissue in comparison with healthy tissue. Ozone Sci Engg12: 65–72.
  12. Washutti J, Viebahn R, Steiner I (1989) Immunological examinations in patients with chronic conditions under administration of ozone/oxygen mixtures. Ozone Sci Engg 11: 411–417.
  13. Zänker KS, Kroczek R (1990) In vitro synergistic activity of 5-fluorouracil with low-dose ozone against a chemoresistant tumor cell line and fresh human tumor cells. Int J Exp Clin Chemother 36: 147–154.
  14. Bocci V, Paulesu L (1990) Studies on the biological effects of ozone 1. Induction of interferon gamma on human leucocytes. Haematologica 75: 510–515. [crossref]
  15. Viebahn-Hansler R (1991) Ozone therapy-the underlying therapeutical concept and models of efficacy. Erfahrungs Heilkunde 4: 40.
  16. Kawalski H1, Sondej J, CierpioÅ‚-Tracz E (1992) The use of ozonotherapy in the nose correction operations. Acta Chir Plast 34: 182–184. [crossref]
  17. Johnson AS, Ferrara JJ, Steinberg SM (1993) Irrigation of the abdominal cavity in the treatment of experimentally induced microbial peritonitis: efficacy of ozonated saline. Am Surg J 59: 297–303.
  18. Gérard V, Sunnen MD (2003) SARS and ozone therapy: Theoretical considerations.
  19. Why consider ozone therapy/oxygen Spa as alternative treatment dallas Fort Worth? [cited in 2010].
  20. Viebahn-Hänsler R (2003)The use of ozone in medicine: Mechanisms of action. Munich. 2003. May 23–25.

Blood Pressure in Healthy Youngsters is modified by Vitamin-D Supplementation

DOI: 10.31038/EDMJ.2019325

Abstract

Objective

Our study aimed to investigate the effect of vitamin D supplementation on blood pressure in vitamin D insufficient young volunteers compared to an age matched control group with sufficient levels of vitamin D. Secondarily we aimed to evaluate the effect of vitamin D supplementation on the RAAS and sympathetic nervous system.

Design

Single centre, Randomised controlled Trial.

Methods

Fifteen vitamin D insufficient and 15 vitamin D sufficient youngsters (18–25 years) were recruited for a clinically controlled trial of 6 months vitamin D supplementation (30 µg/day). At baseline, 30 days, 90 days and 180 days, 24h systolic and diastolic blood pressure, and 25-hydroxyvitamin D, angiotensinogen, renin, angiotensin (I+II), aldosterone, and catecholamines were measured.

Results

The difference between baseline visit and 180 days visit for the vitamin D insufficiency group compared to the control group was; systolic BP (daytime) decreased -6.6 (Interquartile Range 2.4) mmHg (p = 0.009), diastolic BP (daytime) decreased -4.5 (2.1) mmHg (p = 0.03), norepinephrine decreased -0.80 (0.21) nmol/L, (p = 0.0002). There was no effect of vitamin D supplementation on night time systolic or diastolic BP, and no effect on angiotensinogen, renin, angiotensin (I+II), aldosterone or epinephrine.

Conclusion

We observed that 180 days of vitamin D supplementation in normal youngsters with insufficient vitamin D significantly lowered systolic and diastolic BP during daytime. Vitamin D supplementation also significantly lowered circulating norepinephrine. Nothing happened in the control group with normal vitamin D. Hence, it is tempting to conclude that vitamin D acts on BP through SNS as no changes were observed in the RAAS.

Keywords

Vitamin D, Blood pressure, Catecholamines, Normal Youngsters, RAAS.

Introduction

Vitamin D and its importance for skeletal development is well known. The research field of Vitamin D has been broadend even to gene regulation on a grand scale [1]. Recently, Vitamin D deficiency has been found associated with hypertension and several other diseases in epidemiological studies [2, 3] and is a risk factor for cardiovascular mortality [4] and cardiovascular incidents [5, 6] Vitamin D deficiency is prevalent in all ages [7], races [8], geographical regions [9], socioeconomic strata and seasons [10]. Hypertension and vitamin D deficiency are both prevalent worldwide [9, 11, 12] and a causative link between these may potentially have wide public health implications. Hypertension and heart disease are an enormous burden for society. The total direct and indirect costs in 2010 were estimated to $ 273 billion and $ 172 billion respectively in the US [13]. Vitamin D supplementation could potentially be a novel pathway to ease the burden of hypertension, given the low cost and mild adverse effects [14, 15]. Intervention studies with vitamin D supplementation for treatment of hypertension have yielded inconsistent results [16–34]. This inconsistency could be attributed to factors with influence on S-25[OH]D or attenuate the outcome blood pressure e.g. seasonal variation [20, 30], non-cardiovascular comorbidity [16–18, 20–24, 26, 27, 30–32, 34] , medication [16–18, 21–28, 30–32, 34] and normal physiological (S-25[OH]D >50 nmol/L) vitamin D levels [16–18, 21, 24, 26–28, 30, 32, 34] before treatment.

Regulation of Blood Pressure (BP) acts mainly through the Renin-Angiotensin-Aldosterone System (RAAS) and the Sympathetic Nervous System (SNS) [35]. Vitamin D supplementation is associated with the cardiac autonomic tone in healthy humans [36], and could indicate a modulating role of vitamin D in the SNS.

Vitamin D is a secosteroid hormone although it can be obtained through food intake [37]. The main source of vitamin D is represented by its synthesis in the body itself [38]. Vitamin D in its active form, 1, 25-dihydroxyvitamin D3 [1, 25(OH)2D3], crosses the cell membrane, enters the target cell and binds to a specific nuclear vitamin D receptor. The receptor is found in the kidneys, and in mice a decrease in vitamin D is found to increase renin [39]. Vitamin D supplementation could potentially lower renin, which is the first step in the RAAS-pathway and might have a cascading effect on the RAAS-pathway resulting in lowering angiotensin and aldosterone with a lower systemic BP as a result. In rats, vitamin D depletion leads to increases in norepinephrine [40] and increases in systolic BP [41].

To take into account the factors that could blunt or attenuate the effect of vitamin D on BP regulation an investigative setting; with healthy young adults and a group with constant vitamin D concentration acting as control group would be preferable to deal with the seasonal variation. In such a setting, it would be possible to get a more clear view of the effects of vitamin D on BP regulation. To our knowledge, this has not yet been done.

Our clinical trial aimed to investigate the effect of vitamin D supplementation on the BP in two groups; one with vitamin D insufficiency and one with normal levels of vitamin D. The secondary aim was to investigate the effects of vitamin D supplementation on RAAS and the autonomous nervous system, hopefully elucidating possible underlying mechanisms.

Methods

Study Design and Participants

The study was carried out from October 2012 to August 2014 as a single center, parallel-group, clinical controlled trial conducted at the Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark.

Subjects were recruited from a screening of 99 young adults aged 18–25 years. We found 27 potential controls with sufficient vitamin D levels (S-25[OH]D > 80 nmol/L) and 33 with insufficient vitamin D levels (S-25[OH]D <50 nmol/L) and all were invited to participate by e-mail. Participants were excluded if they suffered from diseases or took medication known to interfere with vitamin D as well as pregnancy, hypertension, heart- or kidney disease, diabetes, epilepsy, bone diseases, use of anabolic or systemic steroids

After 15 controls and 15 vitamin D insufficient volunteers accepted the invitation further enrollment was stopped. After enrolment serum 25[OH]D was remeasured to assure that each participant was within inclusion limits of each group on the first day of the study. Each subject’s respective vitamin D level was a result of their lifestyle and genes as all participants were vitamin D so-called naive as only subjects who did not take supplementation was included in the study.

Ethics

We performed the study in accordance to the Helsinki II declaration considering biomedical research. Informed, written consent was obtained from all participants prior to enrollment. The Ethical Committee of the Capital Region, Denmark (ref. no. H-1–2012–023) approved the project.

Intervention

The vitamin D insufficiency group was supplemented to increase the concentration of S-25[OH]D and the control group were supplemented to be kept at S-25[OH]D normal steady state concentration > 80 nmol/L. All participants were supplemented by 30 µg cholecalciferol and 1.200 mg of calcium per day. The participants were instructed to bring all supplied containers and remaining tablets to next visit for compliance estimation.

Study Program

The program comprised four visits, at baseline, after one month, three months, and six months. All visits took place between 08.00 and 17.00; participants had fasted for two hours prior to all visits.

Participants rested 30 min supine position before blood sampling for the assessment of S-25[OH]D, angiotensinogen, renin activity, angiotensin I, angiotensin II, aldosterone, epinephrine, and norepinephrine. Office BP in sitting position was measured and 24-hour ambulatory BP (24hr-AMBP) recording was performed. Vitamin D supplementation needed until next visit was handed to the participants in containers of 180 tablets to be taken three every day (vitamin D3 10 µg and calcium 400 mg per tablet). The second, third, and fourth visit was carried out as the first visit, with the addition of compliance estimation by count of remaining tablets.

Outcome measures

The primary outcome measure was the between-group differences in day and night values from the 24hr-AMBP recording systolic and diastolic BP. The secondary outcome was the between-group comparisons of angiotensinogen, renin activity, angiotensin I, angiotensin II, aldosterone, epinephrine, and norepinephrine.

Measurements

Lifestyle

Through a questionnaire, the participants habit of exercise, smoking and alcohol consumption status was obtained. Smoking: “How many cigarettes have you smoked in the last seven days?” grouped into smoking yes/no. Alcohol: “How many units (12 g) of alcohol have you beendrinking in the last seven days?” grouped into alcohol yes/no. Exercise habits: “How many hours have you spent on exercise in the last seven days?” grouped into three groups; “0–2”, “2–7”, and “7 or more”.

Medical history was obtained through a personal interview to ensure that the subjects were clinically healthy and did not fulfil any of the exclusion criteria. Height was measured using a vertical mounted cm ruler. Weight was measured using an electronic weight (OBH Nordic 6295). Calculation of compliance as the difference in prescribed intake and actual intake divided by prescribed intake of vitamin D supplementation.

Blood pressure measurement

Twentyfour hour ambulatory blood pressure data was recorded with the SpaceLabs 90207 oscillometric unit (Spacelabs, Redmond CA). The default daytime interval was set from 07.00 to 23.00 hr and night time interval was set from 23.00 to 07.00 hr. If participants reported other sleep habits, default values were not used, instead the actual day and night time were used. In the day time BP was measured for every 20 min and every 30 min at night time to fullfil the European guidelines for AMBP measuring at least 14-day time and seven-night time measurements.

Biochemical Analyses

Sympathetic nervous system activity

Sympathetic nervous system activity (SNS) was assessed by measurement of plasma epinephrine and norepinephrine after 30 min. at rest in supine position. Blood samples were obtained in pre-chilled EDTA-tubes and centrifuged at 5 °C for 10 min. at 3, 000 rpm and afterwards stored at -80 until analyzed. Plasma norepinephrine and epinephrine was analysed with a commercial RIA-kit (2-Cat RIA from Labor Diagnostika Nord, Nordhon Germany). Catecholamine was calculated as the sum of epinephrine and norepinephrine.

Renin-angiotensin-aldosterone system

Renin-angiotensin-aldosterone system activity was assessed after 30 min of rest in supine position applying both in-house and commercial available biochemical methods. Blood samples for angiotensinogen were obtained in lithium heparin tubes and measured with the antibody trapping method. Blood sample for renin was obtained in pre-chilled EDTA tubes and measured with RIA based on renin activity. Blood samples 10 mL each for angiotensin I+II was obtained in tubes prepared with inhibitor and measured with an in-house RIA-based method. Blood samples for aldosterone were obtained in tubes with a serum clot activator and analysed with Siemens RIA Coat-a-count.

Serum-25-Hydroxyvitamin D

Serum-25[OH]D was analyzed with the chemiluminescent immunoassay (Liaison® 25-OH Vitamin D Total Assay; Diasorin Inc., Saluggia (Vercelli), Italy).

Statistical Analyses

Sample size calculation for the primary outcome was based on the least relevant effect size of 6 mmHg with an SD = 5 mmHg, α = 0.05, and β = 0.80, we calculated a sample size of 15 subjects for each group to be enrolled.

The continuous data was reported as means and Standard Deviations (SD) when data followed a normal distribution or medians and Interquartile Range (IQR) when they did not. Visual inspection of the continuous data was used to determinate the distribution. For categorical data, percentages were used.

Skewed variables were log (e) transformed before use in parametric statistical analysis.

Group analysis at baseline was performed with student’s t-test or χ2-test. The main analysis of the outcome was by originally assigned groups. We attempted to follow-up on subjects who withdraw by phone, texting, and e-mail. Missing data was assumed missing at random.

A mixed model was applied to take advantage of repeated measurements and deal with missing data. Comparison of simple effects was performed at each visit without separating data in one analysis, to test for the effect of supplementation on visits. For all statistics, (SAS® Version 9.3, Cary, NC, USA) was used. We considered a p-value of <0.05 statistical significant.

Results

Two participants with vitamin D insufficiency and one vitamin D sufficient were excluded on the basis of S-25[OH]D, as they were no longer within the inclusion criteria. Two men and one woman in the control group and two men and one woman in the insufficient group did not complete all four visits, Table 1.

Table 1. Baseline characteristics of participants

Variable

Sufficiency (N = 14)

Insufficiency (N = 13)

P-Value

Age (years) (Mean ± SD)

20.5 ± 2.4

21.7 ± 2.0

0.13¹

S-25[OH]D (nmol/L)(Median (Range)

96.3 (65.3–164.0)

33.3 (10.0–65.8)

Weight (kg) (Mean ± SD)

70.1 ± 11.1

78.4 ± 15.4

0.23¹

Height (cm) (Mean ± SD)

176.4 ± 9.7

174.2 ± 6.0

0.56¹

Office BP systolic (mmHg) (Mean ± SD)

120.6 ± 8.6

126.6 ± 10.8

0.12¹

Office BP diastolic (mmHg) (Mean ± SD)

69.1 ± 5.1

79.0 ± 14.7

0.039¹

Sex

Women

10 (62.5%)

6 (37.5%)

0.18²

Men

4 (36.4%)

7 (63.6%)

Tobacco

No

13 (56.5%)

10 (43.5%)

0.24²

Yes

1 (25.0%)

3 (75.0%)

Alcohol consumption

No

8 (57.1%)

6 (42.9%)

0.57²

Yes

6 (46.2%)

7 (53.8%)

Physical Activity (hours/week)

0–2

1 (11.1%)

8 (88.9%)

0.011²

2–7

5 (71.4%)

2 (28.6%)

7 or more

8 (72.7%)

3 (27.3%)

¹ Mann-Whitney test, ² Chi-square test

Baseline characteristics of the youngsters with sufficient levels of S-25[OH]-vitamin D (controls) and with insufficient levels of S-25[OH]-vitamin D

The first baseline visit was performed in October 2012 and the last follow-up visit was performed in August 2014.The analysis comprised in total 11 males aged 20.4 ± 1.7 yrs and 16 females aged 21.0 ± 2.2 yrs. The baseline characteristics of the participants are given in Table 1. At baseline, no significant differences were found regarding age, height, weight, systolic BP, sex, tobacco, and alcohol consumption between the two groups. At baseline, the group with insufficient vitamin D had higher diastolic BP compared to controls.

The period of supplementation (median [Interquartile Range (IQR)]) for vitamin D was 184 [180–200] days for the insufficiency group and 183 [179–200] days for the control group.

The effect of vitamin D supplementation on S-25[OH]D is shown in Figure 1A. Serum-25[OH]D in the insufficiency group increased from 32.0 (IQR 16.5) nmol/L at visit one to 64.5 (IQR 8.6) nmol/L at visit four. In the control group the change was from 99.9 (IQR 24.1) nmol/L at first visit to 96.1 (IQR 27.1) nmol/L at visit four. The estimated treatment effect of vitamin D supplementation on S-25[OH]D (95% Cl) was an impressive mean increase of 38.1 (Range 25.1 to 51.1) nmol/L for the insufficiency group compared to the controls (p<0.0001).

EDMJ 2019-110 - Lars Thorbjørn Jensen Denmark_F1

Figure 1. Treatment effect of Vitamin D supplementation compared to baseline values

Overall treatment effect over four visits of vitamin D supplementation (ergocholecalcipherol 30 µg/day) in healthy young adults. All BPs are 24hr-AMBP. (A) Treatment effect on S-25[OH]-vitamin D (nmol/L) is significant at visit two (p = 0.0001), three (p<.0001) and four (p<.0001); (B) Treatment effect on catecholamines (nmol/L) is significant at visit four (p = 0.0009); (C) Treatment effect on systolic-BP (mmHg) in daytime (0700–2300 hour) is significant at visit four (p = 0.009); (D) Treatment effect on diastolic-BP (mmHg) in daytime (0700–2300 hour) is significant at visit four (p = 0.03).

The effect of vitamin D supplementation on systolic-BP (24 hr-AMBP, daytime) is shown in Figure 1C.
Systolic BP (24 hr-AMBP, daytime) in the insufficiency group decreased from 124.5 (IQR 12.3) mmHg at visit one to 120.4 (IQR 9.5) mmHg at visit four. In the control group systolic-BP (24 hr-AMBP, daytime) remained unchanged from 115.8 (IQR 8.2) mmHg at first visit to 115.6 (IQR 7.3) mmHg at visit four. The estimated treatment effect of vitamin D supplementation on systolic-BP (24 hr-AMBP, daytime) was a significant decrease of -6.6 (IQR 2.4) mmHg, (p = 0.009) for the insufficiency group compared to the control group.

The effect of vitamin D supplementation on diastolic-BP (24 hr-AMBP, daytime) is shown in Figure 1D. Diastolic-BP (24hr-AMBP, daytime) in the insufficiency group decreased from 73.1 (IQR 10.9) mmHg at visit one to 71.1 (IQR 9.3) mmHg at visit four. In the control group diastolic-BP (24 hr-AMBP, daytime) remained unchanged from 68.1 (IQR 5.4) mmHg at first visit to 69.3 (IQR 4.5) mmHg at visit four. The estimated treatment effect of vitamin D supplementation on diastolic-BP (24hr-AMBP, daytime) was a significant decrease of -4.5 (IQR 2.1) mmHg, (p = 0.03) for the insufficiency group compared to the control group.

The effect of vitamin D supplementation on systolic-BP (24 hr-AMBP, nighttime) is given in Table 2. Systolic-BP (24 hr-AMBP, night time) in the insufficiency group decreased from 106.8 (IQR 11.2) mmHg at visit one to 103.2 (IQR 12.7) mmHg at visit four. Within the control group systolic-BP (24 hr-AMBP, night time) decreased from 105.3 (IQR 7.1) mmHg at first visit to 102.8 (IQR 6.7) mmHg at visit four. The estimated treatment effect of vitamin D supplementation on systolic-BP (24 hr-AMBP, nighttime) was an insignificant increase of in average 0.7 (IQR 3.4) mmHg, (p = 0.8) for the insufficiency group compared to the controls.

Table 2. Effect of vitamin D supplementation on blood pressure and S-25[OH]-vitamin D

Visit no.

1. (Baseline)

2. (30 days)

3. (90 days)

4. (180 days)

S-25[OH]D (nmol/L)

Control

99.9 (24.1)

97.8 (27.6)

94.4 (33.2)

96.1 (27.1)

Insufficient

32.0 (16.5)

54.1 (15.0)

63.2 (16.6)

64.5 (8.6)

Treatment effect

.

+23.6 (5.9)

+37.8 (6.1)

+38.1 (6.5)

Systolic BP, daytime (mmHg)

Control

115.8 (8.2)

115.5 (10.1)

114.2 (9.7)

115.6 (7.3)

Insufficient

124.5 (12.3)

122.2 (9.3)

120.3 (9.3)

120.4 (9.5)

Treatment effect

.

-1.2 (2.3)

-2.9 (2.3)

-6.6 (2.4)

Diastolic-BP daytime (mmHg)

Control

68.1 (5.4)

68.2 (6.7)

69.3 (4.4)

69.3 (4.5)

Insufficient

73.1 (10.9)

70.5 (8.0)

69.2 (9.5)

71.1 (9.3)

Treatment effect

.

-2.8 (1.9)

-3.9 (2.0)

-4.5 (2.1)

Systolic-BP nighttime (mmHg)

Control

105.3 (7.1)

105.5 (10.2)

102.0 (8.4)

102.8 (6.7)

Insufficient

106.8 (11.2)

107.8 (11.4)

103.1 (10.6)

103.2 (12.7)

Treatment effect

.

+3.3 (3.1)

+2.7 (3.3)

-0.7 (3.4)

Diastolic-BP nighttime (mmHg)

Control

56.8 (6.2)

57.3 (4.5)

56.2 (4.8)

57.5 (3.9)

Insufficient

55.3 (7.1)

56.8 (10.8)

51.1 (11.0)

54.7 (10.8)

Treatment effect

.

+2.9 (2.5)

-1.3 (2.7)

-1.3 (2.8)

Controls have normal S-25[OH]-vitamin D at baseline whereas all vitamin D insufficient participants had S-25[OH]-vitamin D below 50 nmol/L at baseline. All BP are 24hr-AMBP. Estimated treatment effect (individual change from baseline compared to groups). Statistically significant (p<0.05) treatment effects are marked with bold. Data presented as median (Interquatile Range)

The effect of vitamin D supplementation on diastolic-BP (24 hr-AMBP, nighttime) is presented in Table 2. Diastolic-BP (24 hr-AMBP, night time) in the insufficiency group remained unchanged from 55.3 (IQR 7.1) mmHg at visit one to 54.7 (IQR 10.8) mmHg at visit four. In the control group diastolic-BP (24 hr-AMBP, night time) remained unchanged from 56.8 (IQR 6.2) mmHg at the first visit to 57.5 (IQR 3.9) mmHg at visit four. The estimated treatment effect of vitamin D supplementation on diastolic-BP (24hr-AMBP, night time) shows a decreasing trend of -1.3 (IQR 2.8) mmHg, (p = 0.6) for the insufficiency group compared to the controls.

For the secondary outcome, we observed an effect of vitamin D supplementation from visit one to visit four on catecholamines. The effect of vitamin D supplementation on catecholamine is shown in Figure 1B. Catecholamines in the insufficiency group decreased from 1.79 (IQR 0.49) nmol/L at visit one to 1.26 (IQR 0.37) nmol/L at visit four, estimated treatment effect in the group was a significant decrease of -0.47 (IQR 0.20) nmol/L, (p = 0.02). Catecholamines in the control group showed a trend of increased from 1.04 (IQR 0.26) nmol/L at visit one to 1.40 (IQR 0.51) nmol/L at visit four, estimated change in the group was 0.33 (IQR 0.21) nmol/L, (p = 0.11). The estimated effect of vitamin D supplementation on catecholamines was a significant decrease of -0.77 (IQR 0.22) nmol/L for the insufficiency group compared to the controls (p = 0.0009).

Norepinephrine in the insufficiency group decreased from 1.61 (IQR 0.48) nmol/L at visit one to 1.19 (IQR 0.37) nmol/L at visit four, estimated effect in the group was a significant decrease in norepinephrine of -0.46 (IQR 0.19) nmol/L, (p = 0.02). Norepiniphrine in the control group increased from 0.94 (IQR 0.25) nmol/L at first visit to 1.40 (IQR 0.51) nmol/L at visit four, estimated effect was an insignificant decrease of 0.36 (IQR 0.19) nmol/L, (p = 0.06). The estimated effect of vitamin D supplementation on norepinephrine was a significant decrease of -0.80 (IQR 0.21) nmol/L, for the insufficiency group compared to the controls (p = 0.0002).

Vitamin D supplementation showed no effect within groups nor overall for angiotensinogen, renin activity, angiotensin I, angiotensin II, aldosterone or epinephrine. No adverse events were recorded through the study.

Discussion

This randomised, controlled trial with vitamin D supplementation in normotensive youngsters over a period of 6 months included 15 controls with sufficient levels of vitamin D and 15 cases with insufficient levels of vitamin D. We observed a significant decrease of both systolic and diastolic blood pressure in the group with insufficient vitamin D levels. Vitamin D supplementation also lowered catecholamines, more specifically a significant decrease in norepinephrine. Conversely, we did not detect any change of the parameters in the RAAS. This points to vitamin D affecting BP through the SNS and not RAAS, contrasting other randomized controlled trials which found lower levels of renin and aldosterone [23, 42, 43].

Most studies investigating vitamin D supplementation on BP show a lack of effect. Looking at meta-analyses with pooled data from 64 randomized controlled trials show that only 8 report of beneficial effects with most studies having been conducted on normotensive participants and a duration of under a year [29, 44–51]. Two large scale trials with vitamin D supplements and a follow-up times of 3 and 7 years show no change in blood pressure [52, 53]. These limitations also apply to our study which investigate normotensive participants over 6 months. Lasting effects beyond the 6 months are unknown, but it is worth noting that during daytime the treatment effect between the control and case groups increased at all visits, indicating that an even greater effect could potentially be seen at further time points.

Vitamin D insufficiency in itself did not activate the RAAS system in our population as the baseline values for the RAAS did not differ between the groups. Rejnmark et al [54] demonstrated in postmenopausal women, that only the concentrations of S-25[OH]D below 80 nmol/L increased 1, –25(OH)2D3 and that Parathyroid Hormone (PTH) are better related to 1, –25(OH)2D3 than 25[OH]D. A similar effect could well be in play here too, as the 25[OH]D concentration in our subjects was not low enough to alter 1, –25(OH)2D3 and stimulate the RAAS-system. The lack of changes in the RAAS system under vitamin D supplementation is a strong argument for the RAAS system not to be modulated by S-25[OH]D in healthy young adults. However, the unchanged RAAS system does not exclude an impact of vitamin D insufficiency on the RAAS activation in already hypertensive and elderly patients.

As expected vitamin D supplementation increased the concentration of S-25[OH]D in the insufficient group whereas the control group remained at a steady state level as intended. This study design handled the seasonal variation well as none from the control group decreased significantly.

Besides the short observation period the study has few limitations. The two groups investigated differed only in physical activity at baseline; the control group had a higher mean physical activity, compared to the insufficient group. This might affect BP and explain the initial difference in total plasma catecholamines. The change over time in total catecholamines is only attributable to changes in S-25[OH]D as this was the only parameter that differed between the two groups between visits. Catecholamines in plasma are a useful measure of the activity of the SNS, despite known limitations. It acts as a systemic index, thus providing no pattern of regional activity of the SNS, i.e. in the heart or in the BP modifying arteries. Another factor to consider, is whether calcium supplementation plays a role in itself. Meta analyses have shown a small effect on BP, especially in patients with insufficient dietary intake [55]. Both groups received calcium supplements, but we cannot rule out the possibility that the patients with insuffient vitamin D could have a greater benefit than the controls.

In conclusion, increase in S-25[OH]D by supplementation might have a clinical relevant effect on lowering the blood pressure in healthy young adults, and might be associated with a modulation of the activity of the SNS but not RAAS. The increase of S-25[OH]D by vitamin D supplementation decreases catecholamines at rest. Further investigations of S-25[OH]D modulation of the SNS is needed to elucidate the importance of S-25[OH]D on BP regulation.

Table 3. Effect of vitamin D supplementation on the Renin-Angiotensin-Aldosterone-System

Visit no.

1. (Baseline)

2. (30 days)

3. (90 days)

4. (180 days)

S-25[OH]D (nmol/L)

Control

99.9 (24.1)

97.8 (27.6)

94.4 (33.2)

96.1 (27.1)

Insufficient

32.0 (16.5)

54.1 (15.0)

63.2 (16.6)

64.5 (8.6)

Treatment effect

.

+23.6 (5.9)

+37.8 (6.1)

+38.1 (6.5)

Angiotensinogen (nmol/L)

Control

1986 (1361)

1953 (1286)

2552 (1829.0)

2471 (1436)

Insufficient

1561 (1044)

1498 (727)

1807 (1466)

2116 (1713)

Treatment effect

.

+137 (290)

+403 (296)

+223 (330)

Renin (mIU/L)

Control

15.5 (11.4)

42.4 (69.0)

20.6 (26.3)

17.0 (12.9)

Insufficient

33.7 (31.2)

34.7 (33.1)

34.6 (19.5)

24.7 (20.0)

Treatment effect

.

+24.1 (12.0)

+3.1 (12.3)

+13.6 (13.9)

Angiotensin I (pmol/L)

Control

40.5 (24.9)

36.0 (35.1)

50.6 (49.3)

30.2 (14.7)

Insufficient

45.8 (34.1)

36.2 (22.5)

68.8 (50.2)

44.4 (29.5)

Treatment effect

.

+1.9 (14.2)

-14.9 (14.2)

-6.5 (15.3)

Angiotensin II (pmol/L)

Control

14.2 (12.9)

12.6 (9.7)

17.1 (13.0)

14.0 (10.1)

Insufficient

17.9 (15.9)

17.1 (12.0)

21.7 (12.6)

17.3 (14.6)

Treatment effect

.

+0.2 (5.8)

-2.5 (5.9)

+0.9 (6.4)

Aldosterone (pmol/L)

Control

244 (152)

211 (145)

448 (466)

318 (234)

Insufficient

197 (82)

302 (189)

291 (169)

224 (138)

Treatment effect

.

-136.7 (99.6)

+105.7 (101.9)

+36.9 (109.5)

Norepinephrine (nmol/L)

Control

0.94 (0.25)

0.79 (0.39)

0.95 (0.32)

1.33 (0.50)

Insufficient

1.61 (0.48)

1.31 (0.61)

1.34 (0.61)

1.19 (0.37)

Treatment effect

.

+0.15 (0.18)

+0.29 (0.19)

+0.80 (0.21)

Epinephrine (nmol/L)

Control

0.08 (0.04)

0.08 (0.07)

0.08 (0.06)

0.07 (0.07)

Insufficient

0.08 (0.03)

0.10 (0.08)

0.08 (0.04)

0.08 (0.04)

Treatment effect

.

-0.01 (0.02)

-0.01 (0.02)

-0.01 (0.02)

Estimated treatment effect (individual change from baseline compared to groups). Statistically significant (p<0.05) treatment effects are marked with bold. Data presented as median (Interquartile Range)

References

  1. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, et al. (2010) A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome research 20: 1352–1360.
  2. Hossein-nezhad A, Holick MF (2013) Vitamin D for health: a global perspective. Mayo Clin Proc 88: 720–755. [crossref]
  3. Autier P, Boniol M, Pizot C, Mullie P (2014) Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2: 76–89. [crossref]
  4. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, et al. (2011) Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 6: CD007470.
  5. Wang L, Song Y, Manson JE, Pilz S, Marz W, et al. (2012) Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. CircCardiovascQualOutcomes. 5: 819–829.
  6. Leu M, Giovannucci E (2011) Vitamin D: epidemiology of cardiovascular risks and events. Best Pract Res Clin Endocrinol Metab 25: 633–646. [crossref]
  7. McKenna MJ (1992) Differences in vitamin D status between countries in young adults and the elderly. Am J Med 93: 69–77. [crossref]
  8. Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, et al. (2013) Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 369: 1991–2000. [crossref]
  9. Holick MF, Chen TC (2008) Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87: 1080S-1086S. [crossref]
  10. Webb AR, Kline L, Holick MF (1988) Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 67: 373–378.
  11. Rahimi K, Emdin CA, MacMahon S (2015) The epidemiology of blood pressure and its worldwide management. Circ Res 116: 925–936. [crossref]
  12. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, et al. (2005) Global burden of hypertension: analysis of worldwide data. Lancet 365: 217–223. [crossref]
  13. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, et al. (2011) Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation123: 933–944. [crossref]
  14. Jones G (2008) Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 88: 582S-586S. [crossref]
  15. Hathcock JN, Shao A, Vieth R, Heaney R (2007) Risk assessment for vitamin D. Am J Clin Nutr 85: 6–18. [crossref]
  16. Gepner AD, Ramamurthy R, Krueger DC, Korcarz CE, Binkley N, et al. (2012) A prospective randomized controlled trial of the effects of vitamin D supplementation on cardiovascular disease risk. PLoSOne 7: 36617.
  17. Witham MD, Price RJ, Struthers AD, Donnan PT, Messow CM, et al. (2013) Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial. JAMA Intern Med 173: 1672–1679. [crossref]
  18. Larsen T, Mose FH, Bech JN, Hansen AB, Pedersen EB (2012) Effect of cholecalciferol supplementation during winter months in patients with hypertension: a randomized, placebo-controlled trial. Am J Hypertens 25: 1215–1222.
  19. Jehle S, Lardi A, Felix B, Hulter HN, Stettler C, et al. (2014) Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study. Swiss Med Wkly 144: 13942. [crossref]
  20. Witham MD, Adams F, Kabir G, Kennedy G, Belch JJ, et al. (2013) Effect of short-term vitamin D supplementation on markers of vascular health in South Asian women living in the UK–a randomised controlled trial. Atherosclerosis 230: 293–299. [crossref]
  21. Forman JP1, Scott JB, Ng K, Drake BF, Suarez EG, et al. (2013) Effect of vitamin D supplementation on blood pressure in blacks. Hypertension 61: 779–785. [crossref]
  22. Kampmann U, Mosekilde L, Juhl C, Moller N, Christensen B, Rejnmark L, et al. (2014) Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency – a double-blind, randomized, placebo-controlled trial. Metabolism 63: 1115–1124.
  23. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C (2001) Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab 86: 1633–1637. [crossref]
  24. Dalbeni A, Scaturro G, Degan M, Minuz P, Delva P (2014) Effects of six months of vitamin D supplementation in patients with heart failure: a randomized double-blind controlled trial. Nutr Metab CardiovascDis 24: 861–868.
  25. Wamberg L, Kampmann U, Stodkilde-Jorgensen H, Rejnmark L, Pedersen SB, et al. (2013) Effects of vitamin D supplementation on body fat accumulation, inflammation, and metabolic risk factors in obese adults with low vitamin D levels – results from a randomized trial. Eur J Intern Med 24: 644–649.
  26. Scragg R, Slow S, Stewart AW, Jennings LC, Chambers ST, et al. (2014) Long-term high-dose vitamin D3 supplementation and blood pressure in healthy adults: a randomized controlled trial. Hypertension 64: 725–730. [crossref]
  27. Sollid ST, Hutchinson MY, Fuskevåg OM, Figenschau Y, Joakimsen RM, et al. (2014) No effect of high-dose vitamin D supplementation on glycemic status or cardiovascular risk factors in subjects with prediabetes. Diabetes Care 37: 2123–2131. [crossref]
  28. Jorde R, Sneve M, Torjesen P, Figenschau Y (2010) No improvement in cardiovascular risk factors in overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern Med 267: 462–472. [crossref]
  29. Kunutsor SK, Burgess S, Munroe PB, Khan H (2014) Vitamin D and high blood pressure: causal association or epiphenomenon? Eur J Epidemiol 29: 1–14. [crossref]
  30. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, et al. (2006) Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 83: 754–759. [crossref]
  31. Arora P, Song Y, Dusek J, Plotnikoff G, Sabatine MS, et al. (2015) Vitamin D therapy in individuals with prehypertension or hypertension: the DAYLIGHT trial. Circulation 131: 254–262. [crossref]
  32. Witham MD, Ireland S, Houston JG, Gandy SJ, Waugh S, et al. (2014) Vitamin D therapy to reduce blood pressure and left ventricular hypertrophy in resistant hypertension: randomized, controlled trial. Hypertension 63: 706–712.
  33. Kienreich K, Grubler M, Tomaschitz A, Schmid J, Verheyen N, et al. (2013) Vitamin D, arterial hypertension & cerebrovascular disease. Indian J Med Res 137: 669–679.
  34. Wood AD1, Secombes KR, Thies F, Aucott L, Black AJ, et al. (2012) Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. J Clin Endocrinol Metab 97: 3557–3568. [crossref]
  35. Boron WF, Boulpaep EL (2003) Medical Physiology. 1 (edn). Philadelphia: Saunders; 2003.
  36. Mann MC, Exner DV, Hemmelgarn BR, Turin TC, Sola DY, et al. (2014) Vitamin D supplementation is associated with improved modulation of cardiac autonomic tone in healthy humans. International journal of cardiology 172: 506–508.
  37. Schmid A, Walther B (2013) Natural vitamin D content in animal products. Adv Nutr 4: 453–462. [crossref]
  38. Bogh MK, Schmedes AV, Philipsen PA, Thieden E, Wulf HC (2011) Vitamin D production depends on ultraviolet-B dose but not on dose rate: a randomized controlled trial. Exp Dermatol 20: 14–18. [crossref]
  39. Li YC (2003) Vitamin D regulation of the renin-angiotensin system. J Cell Biochem 88: 327–331. [crossref]
  40. Baksi SN, Hughes MJ (1984) Alteration of adrenal catecholamine levels in the rat after dietary calcium and vitamin D deficiencies. Journal of the autonomic nervous system 11: 393–396.
  41. Baksi SN (1988) Altered pressor response to norepinephrine in calcium- and vitamin D-deficient rats. Clin Exp Hypertens A 10: 811–832. [crossref]
  42. Schroten NF, Ruifrok WP, Kleijn L, Dokter MM, Sillje HH, et al. (2013) Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure: an open-label, blinded end point, randomized prospective trial (VitD-CHF trial). Am Heart J 166: 357–364.
  43. Grubler MR, Gaksch M, Kienreich K, Verheyen N, Schmid J, et al. (2016) Effects of Vitamin D Supplementation on Plasma Aldosterone and Renin-A Randomized Placebo-Controlled Trial. J Clin Hypertens (Greenwich) 18: 608–613.
  44. Witham MD, Nadir MA, Struthers AD (2009) Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens 27: 1948–1954. [crossref]
  45. Wu SH, Ho SC, Zhong L (2010) Effects of vitamin D supplementation on blood pressure. South Med J 103: 729–737. [crossref]
  46. Lee KJ, Lee YJ (2016) Effects of vitamin D on blood pressure in patients with type 2 diabetes mellitus. Int J Clin Pharmacol Ther 54: 233–242. [crossref]
  47. Elamin MB, Abu Elnour NO, Elamin KB, Fatourechi MM, Alkatib AA, et al. (2011) Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab 96: 1931–1942. [crossref]
  48. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, et al. (2010) Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med 152: 307–314. [crossref]
  49. Beveridge LA, Struthers AD, Khan F, Jorde R, Scragg R, et al. (2015) Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data. JAMA Intern Med 175: 745–754. [crossref]
  50. Golzarand M, Shab-Bidar S, Koochakpoor G, Speakman J R, Djafarian K (2016) Effect of vitamin D3 supplementation on blood pressure in adults: An updated meta-analysis. Nutr Metab Cardiovasc Dis 26: 663–673. [crossref]
  51. Manousopoulou A, Al-Daghri NM, Garbis SD (2015) Vitamin D and cardiovascular risk among adults with obesity: a systematic review and meta-analysis. Eur J Clin Invest 45: 1113–1126. [crossref]
  52. Margolis KL1, Ray RM, Van Horn L, Manson JE, Allison MA, et al. (2008) Effect of calcium and vitamin D supplementation on blood pressure: the Women’s Health Initiative Randomized Trial. Hypertension 52: 847–855. [crossref]
  53. Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, et al. (2017) Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study: A Randomized Clinical Trial. JAMA Cardiol 2: 608–616.
  54. Rejnmark L, Vestergaard P, Heickendorff L, Mosekilde L (2008) Plasma 1,25(OH)2D levels decrease in postmenopausal women with hypovitaminosis D. Eur J Endocrinol 158: 571–576. [crossref]
  55. van Mierlo LA, Arends LR, Streppel MT, Zeegers MP, Kok FJ, et al. (2006) Blood pressure response to calcium supplementation: a meta-analysis of randomized controlled trials. J Hum Hypertens 20: 571–580.

Skin Cancers in Albinos at Surgical Oncology Unit of Donka National Hospital (Conakry)

DOI: 10.31038/CST.2019413

Abstract

Purpose: To determine the frequency of albino skin cancers and to describe the difficulties related to the diagnostic and therapeutic management of these patients in Guinea.

Material and methods: This was a retrospective cohort study on albinos attending Surgical Oncology Unit of Donka National Hospital for skin cancer from March 17, 2007, to December 17, 2016.

Results: We identified the 30 albinoes who presented 41 skin cancer lesions. There were 18 (60.0%) women and 12 (40.0%) men. The average consultation delay was 28.3 months. Patients were housewives in 10 cases (33%), merchants in 8 cases (26.6%) and students in 6 cases (20.0%). The primary sites were the face in 22 cases (73.3%), trunk in 4 cases (13.3%) and neck in 3 cases (10.0%). There were squamous cell carcinoma in 29 cases (96.7%) and sarcoma 1 case (3.3%). The clinical stage was localized in 16 cases (53, 3%), locally advanced in 13 cases (43.3%) and metastatic in 1 case (3.3%).  Wide surgical excision performed in 17 (56.7%) for 28 lesions. Wound closure was achieved by a myocutaneous flap in 15 cases, directed scarring in 7 cases, direct suture in 4 cases and skin graft in 2 cases. After a median follow-up of 8 months, 2 patients presented with relapse and 3 new tumor lesions and 9 (30.0%) died. At 24 months, overall survival was 29.0%.

Conclusion: The incidence of skin cancer is high among albinos. Late diagnosis and inaccessibility to means of treatment are factors limiting the management of this vulnerable group.

Keywords

skin cancers, albinos, squamous cell carcinomas, late diagnosis

Introduction

Albinism is an inherited genetic disorder characterized by hypopigmentation of the skin, hair and / or eyes due to a lack or reduced cutaneous production of melanin [1]. Albinos are very sensitive to sunlight damage to the skin [2]. There are two main types of albinism, oculocutaneous (eyes, skin, and hair) and ocular. Skin cancer is a major cause of morbidity and mortality in albinos. They develop precancerous and cancerous lesions at a young age and suffer from advanced skin cancers in the third and fourth decade of their life [3].

It is clear that there are social discrimination and stigma directed towards albinos. As a result of this social discrimination, they are severely limited in the search for medical care when they have significant deformities following advanced disease [4]. Few data exist on skin cancer in albinos in Guinea. The previous study in our unit showed that skin cancers accounted for 7.8% of cancers and 4 of the 84 cases were albinos [5].

These patients have very little access to prevention and care whereas they should be under dermatological screening. Surgical treatment is the only means of treatment available for healing in our settings. This study aimed to determine the frequency and discuss the management of skin cancers of this vulnerable population at Surgical Oncology Unit of Donka National Hospital.

Material and Methods

Settings

Data collection took place at the Surgical Oncology Unit (SOU) of Donka National Hospital, Conakry University Hospital. This unit, created since 2007, receives albino patients from the dermatology and other departments for the skin cancers treatment.

Study design

This was a retrospective cohort study of albino’s patients with cutaneous cancers at the SOU from May 17, 2007, to December 17, 2016. The consultation records, albino patient records, pathology reports, and the operating protocol register completed data collection forms.

Population and data collection

We included records of albino patients who had histologically confirmed skin cancers among other cases of skin cancer during the study period. Records of albino patients with histologically unconfirmed skin tumors or other types of cancer were excluded.

The socio-demographic data studied included age, sex, ethnicity, occupation, and residence. The history of skin cancer, actinic lesions, smoking, and alcohol consumption was recorded. Infection with the human immunodeficiency virus (HIV) was sought by retroviral serology.

Consultation delay from the moment that the patient observed the lesion and came for consultation was identified. Iterative excision was defined by this done before the patient came to the SOU. Clinical data included clinical appearance, tumor size in centimeters, number of lesions, and primary site.

Histological confirmation was obtained on an incisional biopsy specimen or on a complete excision sample. Histological types were classified according to the World Health Organization (WHO) [6]. Adjacent infiltration of muscles or bone was reported. Regional lymphadenopathies were checked by clinical assessment. The sparing assessment was completed by chest x-ray (looking for pleuropulmonary opacities) and abdominal and pelvic ultrasound (looking for hepatic hypoechoic images). The TNM clinical classification of the International Union against Cancer (UICC) 2010 [7] was used to classify skin cancers in this study.

The types of surgical excision, closure of the operative wound, excision margin status, operative complications, and hospitalization were described. Some patients benefited from palliative chemotherapy (5- Fluoro-uracil and cisplatin). There is no radiotherapy in our country. Follow-up time, rates of recurrence and appearance of new tumor foci, and survival were assessed.

Data analysis

Statistical data were analyzed with statistical package for the social sciences (version 21.0 for Windows, SPSS, Inc., Chicago, IL). Categorical variables were shown as the frequency and percentage (%), and continuous variables were presented as the mean (± standard deviation) and / or median and interquartile range (IQR). Patients lost to follow-up were included in the survival analysis. Factors associated with survival were studied in relation to surgical excision and clinical stage. Survival was calculated according to the Kaplan Meier method. The log-rank test was used to analyze prognostic factors. The cox model was used to search for independent prognostic factors. The test was significant if the p-value was less than 0.05.

Ethical considerations

The data analyzed in this study respected anonymous and confidential principles.

Results

From 2007 to 2016, we recorded 41 albinos with clinically suspected skin cancers. Eleven cases were excluded because of the absence of histological examination. We included the records of 30 patients who had histologically confirmed skin cancer. They accounted for 21.9% of 137 patients with skin cancer at the Donka SOU during the study period. Figure 1 shows the number of cases per year.

CST 2019-103 - Bangaly Traore Guinea_F1

Figure 1. Number per year of albinos among patients presenting skin cancer

Sociodemographic Data

The age ranged from 17 to 76 years with an average of 31.6 years (± 14.0) and a median of 31.5 years (IQR 21.7–45.2). Patients aged 30 and under accounted for 50%. There were 12 men (40.0%) and 18 women (60.0%). Patients were housewives in 10 cases (33.3%), merchants or traders in 7 cases (23.3%) and students in 6 cases (20.0%). The patients were from Conakry region in 8 cases (30.0%), Kindia in 7 cases (23.3%) and Kankan in 6 cases (20.0%). Fulani accounted for 14 cases (46.7%), Mandingo 11 cases (36.7%), Soussous 4 cases (13.6%) and Kissi 1 cases (3.3%).

Risk factors

A patient has been previously treated for skin cancer. An actinic lesion has been found in one patient. Smoking and alcohol consumption were reported in the lifestyle of 5 (16.7%) and 3 (10.0%) patients, respectively. HIV infection was found in one patient.

Clinicopathological features

The median consultation delay was 12 months (IQR 8.5–46.0). Before admission, iterative excision was noted in 3 patients. For the 30 patients, there were 41 cancerous skin lesions or 1.4 lesions per patient. Patients had one lesion in 23 cases (76.7%), 2 lesions in 4 cases (13.3%), 3 lesions in 2 cases (6.7%) and 4 lesions in 1 case (3.3%).

The primary site was the face in 22 cases (73.3%), the trunk in 4 cases (13.3%) and the neck in 3 cases (10.0%).

The clinical aspect was nodular in one patient and ulcero-budding in 29 patients. The tumor size ranged from 1–47cm with a median of 5cm (IQR 3.0–12.0). The tumor infiltrated adjacent muscles in 6 cases (20.0%) and bone in 1 case (3.3%). There was regional lymph node involvement in 7 cases (23.3%) and hepatic metastases in one patient. The clinical stage, according to TNM classification of UICC 2010, was localized in 16 cases (53, 3%), locally advanced in 13 cases (43.3%) and metastatic in 1 case (3.3%). Table 1 presents sociodemographic data, the primary sites, and clinical tumor (T) classification.

Table 1. Sociodemographic data, Primary sites and clinical primary tumor (T) classification (UICC 2010) of skin cancer in albinos (n = 41)

Characteristics

Number

%

Age

–     10–19

–     20–29

–     30–39

–     40–49

–     50–59

–     60 & more

5

8

8

6

2

1

16.6

26.6

26.6

20.0

6.6

3.3

Occupations

–     Housewives

–     Pupils / Students

–     Merchants or sellers

–     Drivers

–     Artist

–     Teacher

–     Veterinarian

–     None

10

6

8

2

1

1

1

1

33.3

20.0

26.6

6.6

3.3

3.3

3.3

3.3

Residence

–     Conakry

–     Kindia

–     Kankan

–     Faranah

–     Boké

–     Mamou

–     Labé

9

7

6

3

2

2

1

30.0

23.3

20.0

10.0

6.6

6.6

3.3

Primary sites

–     Face

–     Trunk

–     Neck

–     Arms

–     Eyelids

–     Multiple

22

4

3

1

1

1

73.3

13.3

10.0

3.3

3.3

3.3

Primary tumor (T) classification

–     T1

–     T2

–     T3

–     T4

–     Tx

4

6

13

2

5

13.3

20.0

43.3

6.7

16.7

The diagnosis based on the histological examination of the biopsy specimen in 20 patients (66.7%) and the excisional specimen in 10 (33.3%) patients. This was squamous cell carcinoma in 29 cases (96.7%) and sarcoma 1 case (3.3%).

Treatment

A wedge surgical excision was performed in 17 patients (56.7%) for 28 lesions. Radical cervical lymph node dissection was performed in the second time in one patient. Wound closure was obtained by a simple suture in 4 cases, cutaneous graft in 2 cases, myocutaneous flaps in 15 cases and directed scarring in 7 cases. Excision margins were free in 7 documented cases. Infection of the operative site (1 case) and delay of healing (1 case) were complications observed. This intervention required hospitalization in 7 cases. The median hospital stay was 6.5 days (IQR 4.5–20.7). Salvage and palliative chemotherapy were performed in 2 and 1 patients respectively. The clinical response to this chemotherapy was disease progression in all cases.

Follow-up

Nine patients were seen once at the consultation. After a median follow-up time of 8 months [95% CI 2.3–13.7], we observed a relapse in 2cases (6.7%), the appearance of new tumor lesions in 3 (10%) patients and 9 (30%) patients had died. Figure 2 shows the old scars and new tumor lesions.

CST 2019-103 - Bangaly Traore Guinea_F2

Figure 2. Old scars and new tumor lesions

Overall survival after a median follow-up of 8 months was 70.0%. At 24 months, overall survival was 29.0% (Figure 3). This survival was correlated with being operated upon (88.2% versus 46.2%) (p = 0.02). It varied according to the stage: 87.5% for the localized stage, 53.8% for the locally advanced stage and none for the metastatic stage (p = 0.056). None of the factors were independent after analysis by the Cox model.

CST 2019-103 - Bangaly Traore Guinea_F3

Figure 3.  Overall Survival of skin cancers in Albinos (n = 30)

Discussion

The limitations of this study were the low number of histologically confirmed cases of skin cancer in albinos. Despite this, we showed the high frequency of skin cancer in albinos, which accounts for about one-fifth of all skin cancers in this study. This frequency was similar according to Kromberg et al [8] in South Africa. It was higher than that of Mabula et al [1] in Tanzania which was 13.2%. In an Imo State plastic surgery department in Nigeria, skin cancer in albinos represented 67.0% [9].

As in other findings [1,3,10], the patients are in their third decade.

The high frequency in the Conakry region and surrounding areas is related to the proximity of the reference services (Dermatology and Oncological Surgery Unit) in the management of skin cancers.

The socio-professional groups involved in this study were those (housewives, tradesmen, students) who were exposed to the sun. Patients working outdoors, under the sun accounted for 75.0% according to Opara and Jiburum [9]. The use of wide-brimmed hats, long-sleeved shirts, scarves on the neck, sunglasses, and sunscreens could reduce the occurrence of cancer in these areas of the body.

Smoking found in some cases would increase the risk of CCS [11]. Actinic lesions was reported only in one patient where is found by Emadi et al [12]in 37.7% of women and 29.1% of men.

HIV infection, diagnosed in a patient, would increase the frequency of cutaneous cancers in albino but the etiopathogenic mechanism is not known [13]. HIV infection was reported in 6.2% of albino patients in the Mabula et al [1] series.

Clinicopathological features

The long delay, varying from 3 to 120 months, was reported by Opara and Kiprono [3,9]. This late presentation was mainly related to poverty and ignorance. Treatment in peripheral hospitals and among traditional healers is mentioned in some studies [1]. Three of them were poor first management in peripheral health facilities, hence the need to improve continuing health professionals training on early detection. The multiple lesions were common in the same patient. The mean number of outbreaks was  1.4 per patient in our study and 1.9 lesions per patient according to Opara [9]. The part of the body (face, trunk, and neck) exposed to the sun, were the most common primary sites. Although none exist in our study, rare cases of localization on the genitals and the lower limbs have been described by Mabula et al [1].

The average size of 5cm is reported in other studies [1, 14].

The diagnosis of cutaneous cancer was confirmed on the histological analysis of the biopsy specimen in 2/3 of the cases and the operative specimen 1/3 of the cases. In the first case, it is often advanced lesions, multiple or from other services with the results. In the second case, these are patients who have resectable lesions, who accept the surgical treatment after assessment; the resection is then both diagnostic and therapeutic.

Almost cases were squamous cell carcinoma in this study. This was reported by several studies [1,3,8,15]. There are no basal cell carcinomas and melanomas, but these forms reported [1,3,9]. In contrast, cutaneous sarcomas in albino are very rare; only one case in this study. Rare cases of sarcomas have been reported [16,17].

Adjacent muscle or bone, and cervical lymph node involvement indicate advanced stages in these patients. These lymphadenopathies were all related to SCC. Mabula et al [1] reported 12.5% of regional lymphadenopathies in 64 patients. In this study, liver metastases were present in one patient whereas Mabula et al [1] described liver, lung, bone and nerve metastases in 6 out of 64 patients.

Treatment

One of the limitations of this study was the small number of patients treated. Our 60% of patients treated were greater than those of a previous study in which 46 of 102 skin cancer patients were treated. [18]. This difference can be explained by the effect of the campaign of early detection and management of albinos in 2014. However, in Africa, black albinos often suffer social discrimination because of superstitious beliefs and the stigma associated with albinism. They are often rejected by their communities, with a resulting delay in the search and treatment of any precancerous or malignant keratosis lesions. Thus, at the time of diagnosis, the lesion is often advanced and has a poor prognosis [13].

Surgery has been reported as the mainstay of treatment for the majority of skin cancers in albinos [19,20]. Wide excision is the most important to prevent local recurrence. Good results can be achieved with radical surgery and optimal surgical margins as well as the reconstructive procedure when needed. In the current study, wide local excision, with skin flap closure or graft was the most performed surgical procedure as in many studies [1,4,9].

One patient underwent cervical dissection for regional lymph node relapse, after treatment of the primary lesion by wide excision. Mabula et al [1] performed a single lymph node dissection among the 64 patients in their study. We did not perform systematic lymph node dissection because we considered that the lymph node would be related to secondary infection. In addition, all lymph nodes decreased after the excision of the primary lesion.

It is often an outpatient surgery. But hospitalization may be needed as for 7 patients who underwent extensive resection and / or to avoid complications while Mabula et al [1] hospitalized more than 90.0% of patients for their treatment. Wound Infection and delayed healing were surgical complications observed in one patient. In addition to these complications, flap necrosis and skin graft loss have been described [1].

Three (3) patients received cisplatin and 5 fluorouracil-based chemotherapy and results were progression disease. Although cases of complete or partial responses have been reported after chemotherapy with adriamycin and platinum salts (carboplatin or cisplatin) [21, 22], there is not enough data to confirm the role of neoadjuvant chemotherapy in locally advanced skin cancers in albinos.

In this study, we had problems to follow-up these patients. The median time to follow up was 8 months. These follow-up problems have been reported by other authors as well [1,9]. Despite these follow-up problems, we were able to assess the local control by the recurrence rate which was 2 out of 17 cases, representing a relapse rate of 11.7%. This rate seems less than that found by Mabula et al [1] which was 30.0%. These differences could be explained by surgical margins status. In this study, surgical margins vary 1–2cm as reported in the previous study on skin cancer surgery in our unit [18]. Our patients did not receive radiotherapy, which is indicated in cases of unresectable locally advanced cancers, in the adjuvant situation and in cases of relapse [1,9]. In addition, radiotherapy can optimize local control after surgical excision of the lesion.

In this study, we noticed the appearance of new tumor lesions in 3 patients. Thus, multiple lesions, relapse, and new tumor lesion mean that albinos can undergo multiple skin surgeries during their lifetime [14].

Approximately one-third of patients died in this study while the mortality was 4 out of 64 patients in Tanzania [1]. This high mortality is related to not being operated upon and has been higher in advanced cases.

Conclusion

The incidence of skin cancer is high among albinos. Late diagnosis and inaccessibility to means of treatment are factors limiting the management of this vulnerable group.

Acknowledgment

We said thanks to Mr. Thierno Boubacar Balde for the patient records availability

Ethics approval and consent to participate: In this retrospective study, data were collected anonymously and confidentially. Patients signed the consent form for the use of data contained in their records.

Consent for publication: Patients signed the consent form for the use of data contained in their records.

References

  1. Mabula Jb, Chalya Pl , Mabula Dm (2012) Skin cancers among albinos at a university teaching hospital in northwestern Tanzania: retrospective review of 64 cases. BMC Dermatology 12: 5.
  2. Ramalingam VS, Sinnakirouchenan R, Thappa MS (2009) Malignant transformation of actinic keratoses to squamous cell carcinoma in an albino. Indian J Dermatol 54: 46–48.
  3. Kiprono SK, Chaula BM, Beltraminelli H (2014) Histological review of skin cancers in African Albinos: a 10-year retrospective review. BMC Cancer 14: 157. [crossref]
  4. Ademola SK (2015) Analysis of skin cancer in albinos Ibadan ; Nigerian J Plast Surg  11: 23–28.
  5. Traoré B, Keita M, Condé M (2016) Skin cancers clinicopathological features in the surgical oncology unit of Conakry Teaching Hospital. Rev CMES santé  2: 2424–7243.
  6. Fritz A, Percy C, Jack A et al. (2000) International Classification of Diseases for oncology. World Health Organization Geneva. Third Edition 2000
  7. Sobin LH, Gospodarowier MK, Wittekind CH (2010) Classification des tumeurs malignes UICC CASSINI 7e édition  173–174 ; 180.
  8. Kromberg JG, Castle D, Zwane EM et al. Albinism and skin cancer in Southern Africa. Clin Genet 1989 36: 43–52.
  9. Opara KO, Jibururum BC (2010) Skin cancers in albinos in a teaching Hospital in eastern Nigeria – presentation and challenges of care; Word J Surg Oncol 8: 73.
  10. Eisenhauer EA, Therasse P, Bogaerts J (2009) New response evaluation criteria in solid tumors: revised RECIST guideline (version1.1). Eur J Cancer 45: 228–247.
  11. Dusingize JC, Olsen CM, Pendeya NP (2017) Cigarette smoking and the Risks of Basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 137: 1700–1708.
  12. Emadi SE, Suleh AJ, Babamamoodi F (2017) Common malignant cutaneous among albinos in Kenya. Med J Islam Republ Iran  31.1
  13. Lekalakala PT, khammissa RAG, Kramer B (2015) Oculocutaneous Albinism and Squamous Cell Carcinoma of the Skin of the Head and Neck in Sub-Saharan Africa,” Journal of Skin Cancer 2015 : 6.
  14. Onuigbo W (2015) The Recognition of recurrent from of albino skin cancer. J cancer Prev Cur Res  3(1)
  15. Asuquo ME, Otei OO, Omotoso J, Bassey EE (2010) Letter: Skin cancer in albinos at the University of Calabar Teaching Hospital, Calabar, Nigeria. Dermatol Online J 16: 14. [crossref]
  16. Graziosi GB, Sbachiero JC, Neto BRC (2014 ) Diagnostique et traitement pour le cancer de la peau chez les albinos : une etude Descriptive. Brazilian journal of plastic surgery 26:1983–5175
  17. Ofilli O (2014) Recurrence of Rhadomyo sarcoma in squamous cell carcinoma in Nigeran pal skinned person (albinos) : A case report. Advanced Research Journal of Medical Sciences  1: 058–060.
  18. Traore B et Lamah L (2017) Outcomes of surgical treatment of skin cancer at surgical oncology of Donka Conakry University hospital. Journal of cancer therapy 8 : 1086–1094.
  19. Hong ES, Zeeb H, Repacholi MH (2006) Albinism in Africa as a public health issue. BMC Public Health 6: 212. [crossref]
  20. Berger E, Hunt R, Tzu J (2011) Squamous-cell carcinoma in situ in a patient with oculocutaneous albinism. Dermatology Online  17: 22.
  21. Chidothe IA, Masamba L. Neoadjuvant chemotherapy in Albinos with advanced skin cancer at a Blantyre Hospital: Case series. Malawi Medical Journal 23 : 97–99.
  22. Mapurisa G1, Masamba L (2010) Locally advanced skin cancer in an albino: a treatment dilemma. Malawi Med J 22: 122–123. [crossref]

Egg and Sperm Donors: Parental Identity Formation

DOI: 10.31038/IGOJ.2019221

 

Infertility is a medical condition that affects many aspects of human life. It does affect one’s relationship with self and consequently will impact one’s self- Identity as a mother or father. Individuals who resort to Assisted Reproductive Technology methods will recognize the emotional impacts, physical, social and as well as economic hardship on their families.

How individual deal with these unexpected emotions, depends on one’s personality style, coping mechanism and external and familial support systems.

Often facing infertility and having to deal with its traumatic impact leads to denial and projection. The traumatic loss of one’s ideal self makes it a challenge for the individual who has to deal with infertility. One cannot rely upon secondary process thinking. The unconscious wishes will always be carrying reason along in the course of the decision making process and what goes into choosing egg or sperm donor.

In considering the psychological implications of ART, here we first discuss the various reproductive technologies available to couples. There are many resources that patients can access to learn about infertility, reproductive facts and Assisted Reproductive Technology. They can also access mental health professionals to help them with their unresolved emotions regarding their infertility, use of egg and sperm donor or surrogate mother.

In the United States, the American Society of Reproductive Medicine (ASRM) has been instrumental in providing specific educational resources to guide people who are facing infertility. American Fertility Association (AFA) is an organization created to educate the public about reproductive disease and support families during struggles with infertility and adoption, (http://www.theAFA.org)

In the United Kingdom since 2005, the child who is the product of egg donation can now find out non-identifying information about its donor at sixteen, and more detailed information, including name and address, when it reaches eighteen. Although the numbers of egg donors didn’t collapse after this, as feared, fewer new donors registered and there has been a shortage as demand has increased – around 1,300 women every year in the UK are treated with donated eggs – with waiting lists of around a year at some clinics, which has resulted in many women and couples seeking treatment abroad. In the UK, the number of women treated using donor eggs has hovered around 1,300 every year since 2007 [1]. (The Guardian, Dec 12, 2012).

The new trend is to air for openness and transparency when individuals resort to egg donors and sperm donors, much similar to what adoption is now a days. More parents do plan to tell such children how they were conceived. There are counseling centers that help couples on how best to do it. Anonymity and secrecy is no longer in fashion. There are still some cases that do not dare to break the secrecy, since struggle with stigmatization, fear of forming weaker attachment bonding and inner conflicts.

Many gay and lesbian couples pioneered openness about using donors; many form relationship with their child’s biological parent.

Today, one in every 100 babies in the U.S is created through some form of in vitro fertilization, or IVF, even many heterosexual couples like to tell their children this modern-day version of the facts of life. (npr report) http://www.npr.org/2011/09/17/140476716/a-new-openness-for-donor-kids-about-their-biology When and how to tell a child about biological genes, depend on the child’s developmental and cognitive capacity to understand the meaning of the information they receive. Dishonesty affects the child’s sense of trust toward their parents. It potentially creates disequilibrium in their psychic function and object relation.

Egg Donors

For woman with premature ovulation failure woman’s ovaries, advanced age, lower ovarian reserve, autoimmune disease, failed IVF, or concerns about genetically transmitted disease, donor egg IVF may be considered. When in-vitro fertilization treatments are not effective, donor eggs can allow an infertile woman to carry a pregnancy to term and give birth. In men with deformed or absent sperms, the use of a technique called, ICSI (Intra Cytoplasmic Inoculation) could potentially present risks to the future child.

Although egg donation is scientifically analogous to artificial insemination with donor sperm, it raises questions concerning the medical risks and potential psychological impact on the mother, couple, and future child. The risks include expense to the woman donating the egg, the risk of carrying multiple babies to term, as well as ethical and legal issues involved in egg donation that have yet to be resolved. There are many psychological, social, and economic issues associated with the use of ART.

During the course of infertility work up, the attention is often focused on the external medical team than an individual‘s mind and unconscious fantasy life. The new infertility techniques help many infertile women to get pregnant, but the interaction between fantasy and reality stimulated by the adult wish for a baby (Pines, 1972) is complicated both before conception and during the pregnancy and the concerns transference feelings toward the donor egg or donor sperm.

After consultation with the reproductive physician, the couple can meet the egg donor though the donor egg coordinator in conjunction with the physician. Psychological issues often appear during the selection process. Some of these cases need help with the entire Egg IVF treatment, donor selection, cycle coordination, egg retrieval, and transfer of embryos.

Unlike their European colleagues, reproductive specialists in the U.S. tend to transfer multiple embryos at a time, resulting in an increased risk of multiple birth pregnancies. Although patients have opportunities to explore the concrete details of IVF available in clinician offices or on websites, they often do not explore their own internal fantasy construct. One example of denial of what reality may present is dealing with multiple babies. There is potential for both pleasure and peril in carrying multiple babies to term and parenting multiples; however pre-warning educative stance could be the most crucial task of reproductive physician and his team.

Sperm Donor

Some men must confront their own infertility issue once the actual infertility like their female counterparts.

In approximately 40% of infertile couples, the male partner is either the sole or a contributing cause of infertility. There may be abnormality related to the volume or amount, motility, and morphology of the sperm. A male fertility work up can involve genetic testing and other hormonal testing. In some cases, no obvious cause of poor sperm quality can be found.

Treatment for male factor infertility may include antibiotic therapy for infection, surgical correction of varicocele (dilated or varicose veins in the scrotum) or duct obstruction, or medications to improve sperm production. In some men, surgery to obtain sperm from the testis can be performed. In some cases, no obvious cause of poor sperm quality can be found. Intrauterine insemination (IUI) or IVF may then be recommended.

When the male infertility is the cause of the problem, individual has the option of choosing a sperm donor. Direct injection of a single sperm into an egg called ICSI, (intra-cytoplasmic sperm injection) may be recommended as a part of the IVF process. In men with deformed or absent sperms, the use of this technique could carry some risks. The physician may recommend using a sperm donor. Insemination with donor sperm may also be considered if IUI is not successful or if the couple does not choose to undergo IVF. Psychologically, men are not immune to devastating feelings of despair when you discover they are infertile.

Men might feel infertility as loss of success—that is as failure or life crisis. As one of my male patients described his feeling of failure, he felt his life came to disequilibrium. He felt a chronic sense of fear and anxiety that felt unending. The recovery from the loss may never reach to a full resolution. The mourning period can linger on for a long time and becomes an unfinished mourning in some cases. A good number of cases are unable to ask for help to process the intense feeling of disappointment to recover from the loss. The feeling of “Why me”, in particular can erodes one’s sense of self-confidence and self-doubt sets in.

Cases

Here we describe three cases in psychodynamic psychotherapy that illustrate the complex psychological ramifications of fertility and the impact of ART.

Nelly

Nelly is a 32-year-old married woman, who came to psychotherapy treatment for depression. She was unhappy in her life, suffered from poor self-esteem and harbored ambivalent feelings towards getting pregnant.

There was no history of childhood disturbances and she was used to being an only child. She had close healthy attachment to her mother. Her developmental milestones were reportedly normal. She had no memory of any other caregivers besides her mother.

Unconsciously she identified with her mother who denigrated her stepfather. Her mother was not a nurturing woman and was often angry with Nelly when she was a young child. In contrast her stepfather was a caring man who showed affection toward her. As a child, she was under the impression that she was conceived out of wedlock. After Nelly turned sixteen, her mother told her that she was conceived with the help of a sperm donor. Her mother refused to tell her whether she had used a sperm bank or the sperm from a friend or acquaintance. Her world suddenly became upside down—not knowing anything about her origin. Her sense of identity was shaken up. Initially shocked by this tightly kept secret. Nelly became depressed when she could not find out the identity of her biological father. She was angry with her mother who concealed the truth from her. She developed an obsession with the thought of wanting to find her biological father.

She needed to know where her chin or nose came from and also why she developed an interest in international relation and cross-cultural psychology. She finally was able to find her father through Internet search after a long detective work. She wanted to solve the puzzle of “Who am I?”

Nelly hoped to forgive her mother for having her out of wedlock, and that someday her mother would tell her about the man whom she got pregnant. She started to understand her mother anxiety about her biological clock and uncertainty about her sense of femininity.

Her mother explained that she was not sure she could marry at age 34 and the clock was ticking away. She did not think she could attract a man to marry her. She decided to use anonymous sperm donor. She told her that her doctor helped her with an anonymous sperm donor. She wanted it to be something like an immaculate conception. Nelly’s mother for reasons of her own did not tell her how she was conceived or where she found the sperm donor. She did not think that far ahead about Nelly’s future inquiry into her root. All Nelly knew was that the man she called Dad was not her biological father. None of her friends knew that Nelly had stepfather.

Once Nelly became aware of the intensity of her chronic anger toward her mother, she decided to get psychotherapeutic help. She felt frozen in her life and could not move forward.

She was in tear one day and said she cannot free herself from her rage. “I don’t understand why my mother did not think about what would happen to me when I had to live in her secret world of lies and deceit! Did she want empathy from me that she was not marriageable and she had to resort to lying to everyone especially to me? I am a person too”.

After she discovered the biological father, she became angry with him as well. One day she related,  “Now I know who was the donor I am angry with him too. It is like staying anonymous and absolved from his responsibility finished his job! I feel miserable. My mother brought me into this world just to please herself by affirming her feminine and fertile self”.

In therapy, she worked on her revived deep sense of shame and narcissistic disappointment. She was ashamed of herself and her mother who lacked self-confidence. She had anxious fantasies that she was joined with her mother eternally and could not find her own autonomous self. She worried her rage would destroy her connection with her mother. Her fear of losing her god-like father of her childhood image of her stepfather mixed with a newly emerging image of this other “father”, these fears turned into an anxiety about her identity diffusion. She felt regret for getting herself into “this mess” without knowing how to get out of it. She wondered about repeating what her mother had done. She fantasized about staying and childless to get revenge from her mother. She did not want to let technology decide her conception. She struggled with her husband’s wish for wanting to have children.

She became aware of her ambivalent feeling about “motherhood” and was willing to work through her childhood wish to conceive and bear a child. She learned to value her academic achievement, which was so much greater than her mother’s without having to feel guilty of surpassing her.

Todd

Todd and Sherry, as a couple, parent of a four-year-old son came to see me because Todd had difficulty relating to their son. He was conceived through using sperm from a sperm donor who was a friend of family and Sherry’s eggs.

Sherry was 35 when after many years of trial to get pregnant; the male infertility was identified as the main factor in failing to conceive. Todd recalled the sense of failure was made infertility so difficult to deal with. It felt like a crisis for him and he went through cycles of hope, fear and despair. It felt for like an emotional roller coaster each time they started a new round of ICSI.  After multiple trials, they came to accept the fact that they had to use a donor sperm. He wanted to use his close friend’s sperm and his wife agreed to that. When Sherry became pregnant, they were able to go through feeling of anticipation and excitement together as a couple. The pregnancy was uneventful their healthy baby boy was born. He was a beautiful boy who did not resemble Todd.

He found himself feeling surprised having noticed some strange feeling toward his infant son and his friend with whom he had a close friendship and working relationship. In retrospect, he started to have doubting feeling about his decision using his friend’s sperm rather going to a sperm bank. It felt right to ask his good friend at that time, but after Sherry gave birth to their son, he noticed he was having many doubts about his ability to be a good father. How could he have ignored his own longing for biological relationship to his child? After all many people went to “Cryobank” and arranged to get donor sperm. He felt his decision asking his friend was a reasonable one at the time. He did assume the biological root did not matter and what mattered was “the end product”. He secretly blamed his wife for rushing to get pregnant. Now that their son is four years old, he looks so much like his friend Peter. He avoids getting together with Peter because he worries his son would show more affinity to Peter as well as Peter towards him.

He wondered if he could ever have the stamina keeping the secret from his son. He worried if he discloses to his son about his genetic root, he would turn away from him. Did he strip his son from the right to know who both of his parents came from? How can he and his wife explain all of these to him?

He argued with himself that his son has the right to know that Todd is not his biological father. Furthermore, he feared his friend Peter would someday reclaim his right as biological father. He kept wondering what would happen to their marriage when all three of them would attend gatherings especially when they would also take their son with them. What if Sherry developed closer connection to Peter and consequently ends their marriage.

The new dilemma he was facing caused the two of them a lot of tension. Sherry communicated to him it was his entire fault that they had to resort to his friend for help. She reminded him that she preferred an anonymous donor. They did yell at each other and it seemed like they could not agree about anything especially when it came down to decisions about the kind of day care their son was to attend or issues around discipline rules. He recalled how he felt mixed, when there was an expectation to be a hand holder when Sherry was going through pregnancy.

He did not have time to think through his decision and was expected to offer Sherry emotional support. He did not know he had come to terms with his own infertility let alone to play a new role supporting his wife. He did not know how he could offer support especially when another man’s sperm was involved in this process. The sense of profound failure as a male was a prevailing feeling. He was there for her when she went through wrenching experience of the harvesting of the ova, but now he felt as if his son was a stranger.  Now only in retrospect, he was able to think more deeply and wondered what effect his consenting to use donor sperm would have had on his sense of father identity and paternity right of their son?

He tormented himself with another question; his fear of seemingly weakened bond with his son. He wished he could have foreseen and prevented psychological complications of his rushed decision.

In his therapy Todd was able to discuss all of his many fears and self-doubt as non-biological father as well as his role as husband to Sherry. He felt he had to prepare himself to be less emotionally reactive or erratic when he encountered his friend. After all, he could not be ungrateful to his friend, since he was an honorable, altruist man who helped to create their son.

He just could not believe that his feelings were going to be so out of control after the baby was born. He agreed to freeze two of Sherry’s embryos for the future use. He resented the thought of having more kids, fearing having to endure the same familiar range of intense emotions. The emergence of a powerful destructive fantasy was explored during this period of his work with me. How could he deny Sherry for wanting to have more babies?

His individual therapy helped him to work through his destructive feelings, mange his intense negative affect, develop a better tolerance, and not acting out on them.  After much individual work, He became interested to start couple therapy. He felt he was in a much better place since he developed a more consolidated sense of himself. He wanted to work on stability of his marital relationship.

From a post therapy contact by phone, Todd appeared that his relationship with his son improved and overall he was able to enjoy a healthy relationship with him. He learned the importance of openness and wanted to tell his son about the sperm donor when he was at a right age to comprehend it’s meaning. His son temperamentally resembled him but not physically.

Emily

Emily a married professional of 45 came to therapy because of conflicts about her desire to become a mother and martial problem. She was doubtful about their capacity to become parents.

She postponed her decision to have a child for many years and suddenly realized time was running fast. Emily was the second child from a family of three children. Her sister was five years older than her and was very popular girl. She could never be like her sister and she felt her mother preferred her sister because they both were brunet and had more in common. Emily was blond and petit. The youngest was a girl who was born eight years after her birth. Emily grew up with a pervasive feeling that she was damaged, a feeling that was reinforced by her over anxious mother throughout her childhood. She was maternal to her younger sister and fiercely competitive to her older sister. Her father drank a lot and used fowl language when she was drunk. She learned to avoid him and his abusiveness.

Emily was an obedient girl who thought she was not intelligent. Her mother constantly compared her to her older sister and her father jokingly called her dumb little blond. She was filled with anxiety and self-doubt. Her family was struggling financially, and she felt inferior to her class -mates who were living in comfort.

In her early adolescence, she befriended a girl from a high socioeconomic class. She could ride in her friend’s car going to school while enjoying the association to her friend’s especial privilege of being driven by her chuffer. She felt envious of her friend and secretly wished she could be her. Her friend’s grandfather, a financially prominent man lived with his Emily’s friend’s immediate family. He touched her chest several times inappropriately during her pubescent years. She recalled those early experiences exciting and at the same time was fraught with shame and guilt. Her friend’s move to another school put an end to it. She liked the attention the old man was giving her by having her sit on his lap. She never told anyone about this.

Emily finished her high school years and was able to enter a prestigious collage. She met her husband in collage and after short few months, they decided to get married. The couple waited for few years before they decided to give it a try to conceive.

Their trials for conception failed for few years and finally the gynecological work up revealed multiple calcified fibromyoma in her uterus.  Her mother also suffered from the same problem. However her mother had her three children before her fibromyoma became problematic.  Additionally Emily’s contributing psychological component complicated further to her infertility problem. Her difficulty conceiving made her feel as though she was “damaged goods”. She could not become a mother unlike her mother and sister. She was bitter and could not accept that her uterine abnormality was an important reason for not conceiving. She felt it was not fair that her sister had children and she could not get pregnant. She was a “virtuous good girl” and her mother relied on her when her family needed help. She felt she was denied something very important, meaning getting pregnant like anyone else. “It was my birth right, it was not fair!”, one day she uttered, and she wanted me to agree with her.

On the other hand, after she found out she could not conceive, she thought “there was a big sign on me like in Scarlet letter that I was Infertile”. The fertility clinic told her she needed to talk to a psychiatrist because her infertility was “psychogenic”. I was going to a full circle. I thought I was grieving. I was so disappointed each time I tried. My husband was not grieving. But, to be fair to him he actually was very supportive of me and left me free to make a decision how to go forward. He even was willing to be childless if I wanted to.

In one of her analytical hours, she said “I must have made myself infertile by being neurotic. See, I am not smart to catch on to things quickly. See, pregnancy may never happen for me. May be I wanted too much like I wanted my friend’s wealth and prestige. I wanted to wear expensive clothes, drive expensive car and marry a rich man. It may want everything or wanting too much, being greedy has to do with not getting what I really want, a family is what I have always dreamt of.” She had tears in her eyes. She was in despair and full of doubt. She continued, “I did not even ask why I needed to talk to a psychiatrist. I followed their advice. Looking back I could tell why I needed to see someone and now I am here to see you in order to understand my ambivalence feeling about motherhood.”

She felt she needed me to help her learning to accept her fate, or maybe she would regain her stamina to pursue other options such as using egg donor or resigning to the prospect of being childless.

She had contemplated using a surrogate mother but wanted to give it a shot to egg donor option and her newly reconstructed uterus a good try (She had gone through extensive myomectomy). Her two IVFs and GIFT (Gamete in the Fallopian tube) procedures were unsuccessful. These failures caused her a great anguish, hopelessness and self -doubt.

She realized how angry she was with her mother who did not empower her and instead made her a damaged woman. She also felt that I was an impotent analyst and that her problem was far more complicated, beyond the scope of my expertise to be able to solve it. She was unsure about the help I could offer her. In the transference I turned in to an “Infertile analyst”. She agreed with my interpretation of how she wished I could have had a magic formula to help her damaged uterus, damaged mind and damaged body. She felt I was letting her suffer in her despair and was being indifferent to her pain. I emerged as a controlling pre-oedipal mother who expected a total obedience and submission.

The decision about using an egg donor and who to ask became an obsession that agonized her for many months. She thought maybe she could ask her younger sister to become her egg donor. She asked herself if her sister could have a second thought about going through the medical procedure. She wanted her child to have her family genes and not to go to a stranger for eggs.

After several month of deliberation, she got her courage up to ask her sister Ann to see if she was willing to be her donor.  Ann was a mother of two and was happily married. She was eager to help her older sister whom she was very fond of. Emily was static when she heard her sister accepted to be her donor egg. We tried to explore the meaning of using the eggs from her sister.

Her desire to use her sister eggs was so strong that she was not interested to explore the meaning of her decision. Her conscious desire was to have her family gene pull with her husband’s sperm than using some stranger whom she did not know. She was set to have her own child and if her sister was willing to give her eggs, it meant that those were like her own eggs. It was like a dress they would share both. That is how she put it with a glee on her face. Shortly after this decision, she started to have fears about her sister’s children who were her child’s half siblings. How could she bear the thought of keeping it secret or have it out in open?

One happy thought countering her fear was “why not to become a big happy family?” She would carry the baby to term and everyone would understand and support her. She also thought she was being greedy to ask for her sister’s eggs, which were not hers. To her it was like stealing! This self-accusation led to an association to an earlier memory about her mother. She recalled how her mother declared one day that how could she feed her children when there was hardly any food at home. Her father, an alcoholic was not helping the family when he spent money on his alcohol. Food was scares and the family had to deal with extreme deprivation.

Together we had done good deal of analytical work to help her with feelings of envy, greediness and stealing charge. She worked hard to overcome her doubt and move forward with her decision to enter into the world of motherhood.

After this unsettling emotional period was over, a much hopeful anticipation to “become a mother” prospect, made Emily overcome her disabling doubts. Her pregnancy was uneventful and she gave birth to a healthy baby girl. She brought her baby infant to one of her sessions. The baby had resemblance to her. She wanted to hear my reassurance   that indeed her daughter looked like her. It was very important to her to hear it from me.

Two years later, after a period of hiatus in her treatment, she phoned to see me for a follow up visit. She was caught by surprise when she began feeling confused about her reaction toward her sister in a holiday family gathering. She felt her daughter seemed to go to her aunt (her biological mother) and she imagined her sister also made it obvious through her non-verbal interaction. She told me that she had never thought about the future encounters and her unexpected emotional reaction. She knew her sister had not revealed to her own two children about having volunteered to be an egg donor to her older sister. Emily was not prepared to talk about it with her daughter and was not sure that she would have wanted to disclose to her.

There was more work for us to do in therapy, exploring the meaning of her motivation giving promise to herself “the promise of anonymity”. She felt competitive toward her sister and felt inferior to her. She struggled with the old feeling about her body that betrayed her.

Discussion

For men like Todd, infertility does not directly affect their traditional and gender role, although it can be profoundly disappointing and be experienced as performance failure and a failure of masculinity, as well. In some cultures, masculinity is directly linked to being able to produce children and as a woman’s value to the man is diminished after her child bearing ends at menopause. There is no parallel to the visible personal bodily changes that the woman experiences in pregnancy.

Both men and women go through the physical and emotional turmoil of infertility. Infertility is both unique and complex. Although children are born through ART, the emotional impact of such reproductive methods is in need of further studies.  The experience of going through fertility work up and ultimately having to go through many medical and psychological phases leading to a successful outcome is very unique for each individual. It can be a lonely and private experience for both men and women. It does affect their sense of which they are and who they imagined in their youth wanted to be. The fundamental value of capacity for creation has been so deeply rooted in sense of bodily self that individual belief systems about her/his sense of identity become challenged. Patient will struggle consciously and unconsciously with the meaning of borrowing eggs or sperms from other living beings.

The intense emotions erupt without knowing how to manage these strong emotions while they go through reproductive procedures.

Analysts and psychotherapists roles offering a holding environment at such trying times are each of these cases presents a complex of social, familial and cultural, unconscious and conscious elements which intern influence the ways in which navigate through the turmoil of their development challenges and unexpected losses. The earlier unconscious conflicts reappear and affect their sense of identity and their couple relationship.

References

  1. The Guardian, UK, Wednesday 12 December 2012
  2. Robert Nachtigall, Elizabeth Mehren (1991) Overcoming Infertility a practical strategy for navigating the emotional, medical, & financial minefields of trying to have a baby. Doubleday Book