Jump to: navigation, search

Male infertility is a cause of the infertility of a couple in approximately 50% of instances. The success rate of treatment of male infertility, with azoospermia, oligospermia, or damaged sperm, etc., with modern medical therapies, has been close to zero. With progress of in-vitro-fertilization techniques, male infertility has become a substantially more serious problem than female infertility. It is not surprising that cell transplantation  has been tried in such desperate situations. VI.BIBLIOGRAPHY [274, 275, 276]

Enormous advances were made in the diagnosis of male infertility, but not so in therapy. A report of 10 infertile males, two of them with infertile wives, and of another infertile female, treated with cell transplantation of placenta, gonads and hypothalamus, with pregnancy in 8 cases, is remarkable, because all these patients had previously been treated for a long time by traditional therapeutic means without success. One of the male patients was found to have an adenoma-like Leydig cell hyperplasia without any seminiferous tubules on testicular biopsy, and no treatment was attempted. In one of two patients that did not father a child, the problem was his wife, that was found by laparoscopy to have a markedly hypoplastic uterus, and refused any further treatment; in the second it was a severe damage of seminiferous tubules, possibly of genetic cause, as his brother had azoospermia. Even in such unfavorable situation spermiogram improved from a few occasional spermatocytes to 10 million, of which 25% had normal mobility, even though 60% was abnormal, after fetal cell transplantation. This favorable situation lasted 3 months but them spermiogram dropped back to an original state and further cell transplantation did not trigger any response.

Four detailed case histories describe a clinical handling of such patients as individuals and as married couples. Two of the patients were victims of mumps orchitis, one at the age of 20, who following fetal cell transplantation fathered 3 children, and the second at the age of 29. Since the 2nd patient was already a father of 2 children, he served as a temporary control, as his cell transplantation was postponed for 5 months to prove beyond any reasonable doubt that spontaneous regeneration did not take place after orchitis. Two months after fetal cell transplantation his wife became pregnant again. Author advises that two weeks after orchitis no spontaneous regeneration can take place anymore and at that point a patient with mumps orchitis should be treated by cell transplantation without any further delay.

Cell transplantologist must not confuse hormone therapy with fetal cell transplantation. Endocrinologists usually overdose patients, and that is highly inadvisable with cell transplantation.. If the 1st cell transplantation was not successful, the 2nd must be postponed for 6 – 9 months. Another error is to implant cell transplants of testis only. It is mandatory to add hypothalamus and placenta, and possibly adrenal cortex and anterior pituitary, to balance out the regulatory circuits.

One of these male patients with a biopsy proven nearly complete atrophy of the seminiferous tubules, that was turned away by a university clinic as untreatable, was impotent as well. After fetal cell transplantation the potency was restored, but sperm count showed only 3 live and 3 dead sperms. The patient was subsequently treated with Mesterolone and chorionic gonadotropin, sperm count rose to 12.4 million, conception took place, and baby girl was born. Subsequently the patient had azoospermia again. The 2nd fetal cell transplantation was done, and without a success like before, so that another course therapy by Mesterolone and chorionic gonadotropin was planned. In a later follow up-report the author informed that the patient fathered a second child. Author advises that in seemingly hopeless cases before an extensive hormone therapy is begun, all infertile male patients should be treated by cell transplantation in order to stimulate regeneration of testicular epithelium. After fetal cell transplantation it is important to watch for the improvement of sperm motility, as it always precedes the increased sperm count, and pay attention to other ongoing treatments ordered by other physicians, and regularly examine the testicles as they can be palpated easily, and usually in 4 weeks after cell transplantation they become full, tense and tender, i.e. with regenerated seminiferous tubules.

30 years’ old female with no children after 3 years of marriage had bilateral tubal narrowing and underwent bilateral tuboplasty. Her husband had low sperm count with 70% immobility. Subsequently, fully synchronized, her ovulation was suppressed for two cycles and husband received fetal cell transplantation. The conception was prompt and the couple had eventually 3 children.

The sole female patient treated without a husband, 20 years old, had oligomenorhea for 5 years, suffered from erythema nodosum, and 6 years later developed sarcoidosis. For 3 years she took a variety of traditional infertility treatment without success. Cell transplantation of placenta, and ovary, lead to pregnancy, and altogether 3 children.

This success triggered a similar therapeutic programm for infertile bulls at the Veterinary Medical school in Munich with comparable results. VI.BIBLIOGRAPHY [314]

This is a loose continuation of the previous report. By 1979 the author treated 17 married infertile couples that conceived 29 children. After 1979 only 23 males were treated by fetal cell transplantation of testis, placenta, hypothalamus, anterior pituitary, adrenal cortex, three of them fathered a child, 10 did not come for a follow-up and 11 came to one follow-up examination with a spermiogram only: 2 had 15x increased sperm count, one had 8x, one 7x, one 5x, two had 3x, three had 2x, and one had no change in sperm count. One patient had a fructose deficiency, and after two cell transplantations there was an increase of sperm count above normal limit. In 7 patients the sperm mobility significantly improved. It is felt that if the 1st cell transplantation does not give any clinical effect that it is useless to continue with treatment. In the 2nd cell transplantation testis and adrenal cortex only suffice. VI.BIBLIOGRAPHY [315]

Physiology of androgens:

Secretion of gonadotropin-releasing hormone from hypothalamus triggers a release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), while prolactin inhibits it. LH stimulates the secretion of testosterone in Leydig interstitial cells, and that through negative feedback inhibits release of gonadotropin-releasing hormone and luteinizing hormone. FSH supports in Sertoli cells of testis a production of inhibin, which inhibits production of FSH, as well as of androgen binding protein, dihydrotestosteron, and Muller inhibitory factor.

Testosteron is necessary in males for the growth of penis, scrotum and tubuli seminiferi, secretion of prostate, i.e. lowering of ejaculate viscosity, and of tubuli seminiferi, e.g. addition of fructose and prostaglandins, as well as secretion of axillary and inguinal sweat glands, growth of muscles, bones, larynx, pubic, axillary, facial, and chest hair growth, and male pattern baldness. It supports libido and aggressive behaviour. It lowers HDL-cholesterol and fertility.

Lack of androgens is due to lack of gonadotropin-releasing hormone, normally released in pulses, due to disturbances of hypothalamus, i.e. radiation, circulatory dysfunction, genetic defects, inhibition of release of LH and FSH due to pituitary disturbances, i.e. trauma, infarctions, autoimmune diseases, hyperplasias, etc., or due to low production of androgen in testes because of genetic disturbances, or serious systemic diseases.

A 45 years old widower with no children from the first marriage, re-married 38 years old female, and expected pregnancy did not take place. Spermiogram showed lower count and abnormal motility. After the failure of orthodox therapies, including psychological, the patient decided for an alternative treatments, by electroacupuncture and homeopathy. After an impotence was admitted, fetal cell transplantation of testis, mesenchyme, thymus, exocrine pancreas, stomach/intestine, liver, was carried out. Two months later the patient had a normal erection, 10 months later his wife became pregnant and a baby girl was born. VI.BIBLIOGRAPHY [312]

Fetal precursor cell transplantation of testis, hypothalamus, diencephalon, pituitary, adrenal cortex, placenta, prostate, liver, mesenchyme, is indicated in all cases of male infertility even in cases of azoospermia if testicular biopsy is normal, or there is a diffuse/focal tubular testicular atrophy but some reproductive epithelium still exists. If there is aspermia on spermiogram, and a total fibrosis by histologic examination, then cell transplantation is useless.

We developed a technique, which should be tried in some well selected patients. This protocol requires a full cooperation of an infertility clinic. After a complete diagnostic evaluation, fetal precursor cell transplantation is carried out in order to stimulate the 'hypothalamus - pituitary - testes axis', to accomplish an immunomodulation if necessary, and to treat any other existing disease of a patient.  After a month or so the patient’s ejaculate must be collected every week for 4 weeks, and inspected for normal, mobile, spermatozoa. If any such spermatozoa are found, they have to be concentrated, and frozen. When a sufficient quantity of spermatozoa is accumulated, an artificial insemination is carried out, and repeated as necessary.

As a male is usually not happy with the idea that his child would not be really his, before electing to use a sperm of a donor for in-vitro-fertilization, a trial of the above method is worthwhile.

Clinical protocol for fetal precursor cell transplantation treatment of male hypogonadism

Parameters to be followed in patients before and after fetal precursor cell xenotransplantation, and the frequency:

General: every 3 months or as clinically necessary

i/ clinical status of pubertal process: symptoms and signs

ii/ measurement of body proportions, body hair and genitalia development

iii/ evaluation of libido and potency

iv/ x-rays of sella turcica

v/ CT scan or MRI of sella turcica and surrounding part of brain

vi/ semen analysis

vii/ buccal smear and/or karyotype if necessary

viii/ testicular biopsy if ever necessary

ix/ test of nocturnal penile tumescence

x/ duplex ultrasonography with intracorporeal injections of vasoactive agents

Immunological: once a month x3, then every 3 months:

i/ total lymphocytes

ii/ T-lymphocytes (CD3+)

iii/ T-helpers (CD4)

iv/ T-suppressors (CD8+) and CD4/CD8

v/ NK (CD16)

vi/ B-lymphocytes (CD22 and CD19)

vii/ serum IGG, IGA, IGM

viii/ serum complement (CH50)

ix/ antisperm antibody test

Laboratory: once every 3 months or as clinically necessary:

i/ T3, T4, TSH by radioimmunoassay

ii/ thyrotropin releasing hormone stimulation test

iii/ serum prolactine

iv/ serum total and free testosteron and dehydroepiandrosterone sulphate

v/ chorionic gonadotropin stimulation test

vi/ clomiphene citrate stimulation test

vii/ serum FSH and LH levels

viii/ gonadotropin-releasing hormone stimulation test

ix/ 24-hour urine for free cortisol,17-hydroxycorticosteroids and 17-ketosteroids

x/ ACTH stimulation test or Metyrapone test

xi/ corticotropin-releasing hormone test

xii/ hypo-osmolar swelling test for integrity of spermatocyte plasma membrane

xiii/ hemizona assay: sperm binding to oocyte zona pellucida surface receptors

xiv/ sperm penetration essay of oocytes

Frequency of office visits: 4 weeks and 48 hours before fetal precursor cell xenotransplantation, 24 hours after and then once a week for the first month after fetal precursor cell xeno-transplantation, once a month thereafter.

Ovarian insufficiency has been treated succsesfully by cell transplantation for decades but it has involved mostly patients with a physiological menopause. In the last two decades a hormone replacement therapy by estrogen and progesterone became the treatment of choice for a menopause. Today, a growing concern that synthetic estrogen causes a variety of side effects, including cancer, brings back the well established fact that fetal cell transplantation is safer than aspirin, and definitely does not cause cancer. In principle, fetal precursor cell transplantation of ovary, placenta, adrenal cortex, hypothalamus, thyroid, epiphysis, entire pituitary including infundibulum, pineal gland, is recommended.

Premature menopause,  where standard hormone replacement therapy has failed, is another group of diseases where fetal precursor cell transplantation has been used during the last 10 years with remarkable effectiveness.  The number of patients with early menopause treated by fetal precursor cell transplantation cannot be compared with those in the usual 'menopause'. VI.BIBLIOGRAPHY [277, 278]

The frequency of premature menopause has been increasing with such a speed in the 'civilized' world that there is a talk about a real 'epidemic'. It is apparently due to the stress and pressures of high level jobs, requiring long hours, intense competition, hectic lifestyle, etc., along with the ideal ‘thin’ body shape, that so many young women in their early thirties stop menstruating, and soon develop classical symptoms of menopause, and of its complications. In not so rare instances it is due to the prolonged use of birth control pills. The high incidence of genital infections among the young people of our modern society plays an unspoken part.

Physiology of female sex hormones:

Gonadotropin-releasing hormone of hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteotropic hormone (LH) from anterior lobe of pituitary in pulses.

In female FSH supports maturation of follicles and estrogen production in granulosa cells of follicles. Estrogen stimulates at first additional release of gonadotropins up until the full maturation of follicle and creation of corpus luteum, i.e. positive feedback, but from that point on inhibits any further release of gonadotropins, i.e. negative feedback.

LH triggers ovulation and supports the creation of corpus luteum at mid-cycle, and corpus luteum produces progesterons, which inhibits any further release of gonadotropins as well.

As a result of inhibition of gonadotropin release the concentration of estrogens and progesterons decreases, and that eventually leads to menstruation.

Theca cells of corpus luteum produce also androgens.

Estrogens stimulate the development of primary female sexual characteristics, i.e. change of Muller ducts into Fallopian tube, uterus and vagina, as well as of secondary female sex characteristics, i.e. mammary glands, fat distribution, axillary and pubic hair growth (along with androgens), psychic development toward femininity. In uterus they stimulate mucosal proliferation, in uterine cervix and vagina lower the viscosity of cervical mucus and thicken vaginal mucosa , and break down glycogen to lactic acid with help of vaginal microflora. In mammary glands estrogens support development of mammary ducts. They support production of protein, HDL and VLDL, and inhibit levels of LDL, and thereby lower the risk of atherosclerosis. Estrogens increase blood coagulation, retention of salts by kidneys, and bone mineralization.

Progesterons support in uterus the maturation and secretory activity of mucosa and lower the contractility of musculature, and inhibit the motility of Fallopian tubes. In uterine cervix and vagina they increase the viscosity of cervical mucus, narrow cervical canal, inhibit proliferation of vaginal epithelium, and mammary glands support development of alveoli. They increase the basal metabolic rate, body temperature, trigger hyperventilation and lower the sensitivity of peripheral cells to insulin, and decrease the production of cholesterol and plasma concentration of HDL and LDL.

Lack of estrogens and progesterons is often due to lowered release of gonadotropin-releasing hormone (excessive stress, poor nutrition, professional sport, serious systemic diseases, neurotransmitter dysfunction), or of gonadotropins (hemorrhage, infarction, inflammation, trauma of pituitary gland).

With growing ovarian production of androgens the release of FSH is inhibited, maturation of follicle blocked, and that leads to polycystic ovaries.

Decreased release of gonadotropins is often caused by an increased concentration of prolactin due to prolactin producing tumors, lack of inhibition of prolactin secretion, anti-dopaminergic drugs, or by hypothalamic damage: trauma, radiation, degenerative or inflammatory diseases, defects of biosynthesis.

Decreased production of estrogens and progesterons by ovaries can be due to developmental anomaly of ovaries, damage from radiation or cytostatics, or enzymopathy.

Lack of female sex hormones makes normal menstrual cycle impossible, and the same applies to the excess of female sex hormones, usually a result of use of anti-conception drugs. With lack of estrogen there is no proliferative phase in uterine mucosa, and thereby the progesterons cannot bring it to maturation. In either case the females are infertile. There is amenorrhea, less pronounced secondary sexual characteristics, tendency toward vaginal infections, osteoporosis, and increased risk of atherosclerosis.

Gynecologists have observed that for some reason ~ 50% of patients with early menopause do not respond well to the usual hormone replacement therapy with estrogen and progesterone, for reasons unknown. This was the reason to investigate the treatment of such non-responding patients with cell transplantation.

In the April 1994 issue of the Bulletin of Experimental Biology and Medicine, Volume 117, an official journal of the Russian Academy of Medical Sciences, there are three articles about the results of our controlled study of the treatment of post-castration syndrome, i.e. ‘early menopause’, by transplantation of human fetal tissues as compared with hormone replacement therapy, and a control group.

Our controlled study, actually a dissertation for ‘Doctor of Science’ degree at Russian Research Center of Obstetrics Gynecology and Perinatology of Ministry of Health of Russian Federation, included 150 patients from 33 to 43 years of age, that underwent a bilateral total oophorectomy for variety of indications, but not cancer, and were in early menopause, and their ovaries were absent as proven by ultrasound. Of this group 45 patients were treated by human fetal tissue transplantation, 50 patients by a hormone replacent therapy, and 55 patients received a placebo. Cell transplantation of ovary, adrenal cortex, hypothalamus, placenta, spleen, liver, had a 100% success rate.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

As seen on Figures 1 - 8 the serum levels of  estradiol, progesterone,  testosterone, follicle-stimulating hormone (FSH),  luteinizing hormone (LH), cortisol,  thyroid-stimulating hormone (TSH),  prolactine, all at menopausal levels before fetal precursor cell transplantation, start to return to normal after 4 weeks and remain at low/normal serum levels for 4 – 5 months after the 1st fetal precursorcell transplantation. At that time the level of hormones starts to return to menopausal levels again, but never reaches their levels from before fetal precursor cell transplantation.

Immediately after the 2nd cell transplantation the level of all hormones goes back to nearly normal levels and stays there for 6 – 9 months.  With each subsequent fetal precursor cell transplantation the duration of clinical effect becomes longer.

Level of prolactine was normal before the 1st cell transplantation and remained so at all times.

The best results were in 4 patients where cell transplant of ovary was implanted endoscopically into an ovarian stump. In two cases an ultrasound examination 6 weeks after cell transplantation proved a temporary presence of follicles.

This was a very comprehensive study, that included measurements of bone density, evaluation of central nervous system function and autonomous nervous system function, and breast examination. VI.BIBLIOGRAPHY [317, 318, 319, 320]

The bone density dropped in control group during 12 months of observation from 90.5% to 87%, while in patients after two cell transplantation treatments it increased from 90.5% to 93%.

In 38 patients of the group treated by fetal cell transplantation a functional state of autonomous nervous system was evaluated. One months after the 1st cell transplantation patients reported positive changes of general condition, work capacity, mood, sleep, cessation of overreactions to the nuisances of everyday life and excessive concentration on their illness. Reactive anxiety tests dropped from 20 to 9 points. Plethysmographic responses were improved. Responses to cold and mental arithmetics in terms of blood pressure, heart rate, skin galvanic reflex, were improved for the first two months but returned back to the original state in 5 – 6 monts along with the return of hormonal indices. The improvement of autonomous nervous system was attributed to the improved hormonal state after cell transplantation. VI.BIBLIOGRAPHY [318]

In 45 patients of the group treated by fetal cell transplantation an EEG study was carried out before and 1 month after the 1st cell transplantation both in the calm state and then during the functional overload of photostimulation, constant light and sound exposure, hyperventilation. Approximately 2 months after cell transplantation there was a remarkable improvement of EEG in terms of an adjustment of the relationship between brain cortex and brain stem, a reduction of a-rhythm index, and increased ß-activity index. Reactions to light stimuli and the function of brain cortex improved. During 6th months after cell transplantation all improvement disappeared and the pre-transplantation status was restored. VI.BIBLIOGRAPHY [319]

Clinical and mammography study of breasts was carried out in 45 patients of the group that received cell transplantation. Drastic drop of estrogen and progesterone and increased gonadotropin levels before the 1st cell transplantation caused involutional process of the breast in all patients regardless of the patient’s age. Re-examination 6 – 8 months after cell transplantation showed an improved skin turgor, but the volume of the glands remained the same on mammography. VI.BIBLIOGRAPHY [320]

Overall, a a judicious combination of fetal precursor cell transplantation with a hormone replacement therapy can bring patients with premature menopause back to normal.

In animal experiments Levander proved that implants from tissues obtained from a dead organ could trigger responses and new formations of corresponding tissues in the mesenchyme surrounding the implantation site by a process of induction. It is certain that an explanation of these phenomena is not a continued growth of the implanted cells or cell complexes. Levander observed these new, induced, organ-specific formations also after the implantation of endometrium, thereby making an important contribution to our knowledge of the pathogenesis of endometriosis.

In hundreds of experiments with rabbits it could be demonstrated that the subcutaneous injection of various tissues induced only the formation of the tissue that corresponded exactly with the implanted tissue, i.e. local tissue generation is organ-specific.

Levander demonstrated pictures of endometrium implantations which always showed new formations of endometrioid tissue.

Bernhard verified Lavender’s experiments by histological studies to find out whether the implants also have a histologically demonstrable organ-specific, organotropic ‘distant effects’ upon internal organs. He reproduced experiments with endometrium and proved that the implantation of other organ tissues does not induce the growth of endometrial tissue. He proved this by a process of exclusion, since implants of liver, spleen, lungs, heart, and placenta, did not produce any new endometrioid tissue formation.

Organotropic, organ-specific, distant effect on the uterus of the castrated rabbit was seen. Castrated rabbits received implantations of rabbit endometrium taken from pregnant rabbits. In all experimental series a regeneration of mucosa with distinct glandular formation was observed in the recipient animal.These effects were not produced by hormonal influence as it was proven that cell transplants did not contain a demonstrable amount of estrogen. VI.BIBLIOGRAPHY [323]

It has occurred frequently in the 85+ years' history of fetal precursor cell transplantation, that it has been used in those patients where all known therapies had failed. Among those were patients with intractable endometriosis. In our study of 6 such patients treated by cell transplantation of ovary, adrenal cortex, hypothalamus, placenta, uterus, at the Russian Research Center of Obstetrics, Gynecology and Perinatology of Russian Academy of Medical Sciences, the success rate was 100% as all patient were pain-free for 6 – 10 months and had normal periods.

Many patients have undergone hysterectomy for uterine myomas because 'the patient was of the age when it makes no difference', just to learn that their husbands left them because of the lack of uterus, or because they gained too much weight after the operation, etc.  Patients with myomas of the uterus, in whom surgery was contraindicated, or who refused it, have been treated by fetal precursor cell transplantation of prostate, ovary, adrenal cortex, hypothalamus. The size of uterine myomas was decreased by such therapy, and thus hysterectomy could have  been avoided or postponed.

In female infertility there are clinical situations, when in-vitro-fertilization had not worked, and repeatedly so, for reasons that cannot be elucidated by even the most sophisticated diagnostic methods.  In our experiemce fetal precursor cell transplantation of ovary, adrenal cortex, hypothalamus, placenta, liver, is to be considered in such instances, followed in 4 weeks by another in-vitro-fertilization attempt.  Even though the medical reports about such approach are hard to find, this has been a well guarded secret of many gynecologists dealing with infertility long before in-vitro-fertilization came into existence.

Our study on treatment of habitual abortion of adrenal etiology by porcine fetal precursor cell transplantation in 23 patients, with 96% success rate, i.e. 22 out of 23 patients delivered healthy children, proved that routine use of hormones of adrenal cortex, with high risk to the mother and fetus, is not necessary. Habitual abortion due to impaired adrenal function is found in 26.6% of patients with delayed diagnosis, and in 15 – 20% of patients when diagnosis was known before conception or made in early pregnancy. The most common causes of habitual abortion are genetic 21-hydroxylase or 11-hydroxylase deficiencies, and Addison’s disease of various etiology. The usual treatment by gluco- and mineralo-corticoids is fraught with the risk of developmental defects of the fetus, in particular cleft lip and palate, when the treatment had to start in the 1st trimester of pregnancy, or of overall growth retardation, when the treatment had to be carried out throughout the whole pregnancy. The frequency of side effects with the chronic use of glucocorticoids is nearly 50%.

Over the period of 5 years 23 patients, aged from 22 to 38 years, with a history of 1 to 9 spontaneous abortions, diagnosis of Addison’s disease in 12 patients, or congenital hypocorticism with hyperadrogenism in 11 patients, and a threatened abortion, underwent fetal precursor cell transplantation of porcine adrenal cortex prepared by tissue culture method at various stages of pregnancy, from 5 to 31 weeks. Implantation was under the aponeurosis of rectus abdominis muscle. A full term delivery of a healthy child of average weight 3,100 gm took place in 22 out of 23 patients. One patient had a spontaneous abortion at 16 weeks. Cortisol level in the late stages of pregnancy was normal. Three detailed case histories are included. VI.BIBLIOGRAPHY [316]

Dysfunctional uterine bleeding of unknown cause, when diagnostic steps do not point to a successful treatment, is occasionally an indication for fetal precursor cell transplantation of adrenal cortex, liver, exocrine pancreas, anterior lobe of pituitary, placenta, usually after surgical or medical D&C has stopped the irregular bleeding. VI.BIBLIOGRAPHY [328]

Clinical protocol for fetal precursor cell transplantation treatment of premature ovarian failure and female infertility

Parameters to be followed in patients before and after fetal precursor cell xenotransplantation, and the frequency:

General: every 3 months or as clinically necessary:

i/ clinical status of hyperandrogenism and galactorrhea, if present

ii/ measure body proportions, body hair, breast and genitalia development

iii/ clinical status of pubertal process: symptoms and signs

iv/ x-rays of sella turcica

v/ CT scan or MRI of sella turcica and surrounding part of brain

vi/ ultrasound of ovaries, serial ultrasound of ovaries, ‘folliculogram’

vii/ chromosomal evaluation, if necessary

viii/ progestational challenge test

ix/ basal body temperature

x/ endometrial biopsy during the late luteal phase

xi/ hysterosalpingogram

xii/ hysteroscopy

xiii/ timed cervical mucus examination

xiv/ post-coital test

Immunological: once a month for 3 months, then every 3months

i/ total lymphocytes

ii/ T-lymphocytes (CD3+)

iii/ T-helpers (CD4+)

iv/ T-suppressors (CD8+) and CD4/CD8

v/ NK (CD16)

vi/ B-lymphocytes (CD22 and CD19)

vii/ serum IGG, IGA, IGM

viii/ serum complement (CH50)

Laboratory: once every 3 months or as clinically necessary

i/ CBC, sedimentation rate, serum proteins, A/G ratio, serum Ca, P

ii/ T3, T4, TSH by radioimmunoassay

iii/ thyrotropin releasing hormone stimulation test

iv/ serum estradiol, progesterone, testosterone, dehydroepiandrosterone

v/ serum 17-hydroxyprogesterone

vi/ prolactine level

vii/ serum FSH and LH levels

viii/ gonadotropin-releasing hormone stimulation test

ix/ 24-hour urine for free cortisol,17-hydroxycorticosteroids and 17-ketosteroids

x/ ACTH stimulation test or Metyrapone test

xi/ corticotropin-releasing hormone test

Frequency of office visits: 4 weeks and 48 hours before fetal precursor cell xenotransplantation, 24 hours after and then once a week for the first month after fetal precursor cell xeno-transplantation, once a month thereafter.


O.V.D., born 1960, white female, developed endometriosis at the age of 24. None of the treatments could control the disease, and patient became disabled. At the age of 30, she decided to accept a major surgical procedure: a removal of all pathologic tissue, and that included bilateral total oophorectomy. Postoperatively the patient started a hormone replacement therapy, but regardless of what type of estrogen and progesteron she took, or which program of simulation of the natural cycle of estrogen and progesteron intake her gynaecologists tried, she had persistent severe symptoms and signs of menopause: hot flashes, fatigue, irritability, insomnia, memory loss, lack of concentration, headaches, palpitations, tachycardia, bone pain, atrophic vaginitis, with dyspareunia and lack of libido, and weight gain.

Physical examination on 10/11/94 revealed mild obesity, sallow complexion, atrophic breasts, atrophic vaginitis, varicose veins. X-rays of sella turcica was within normal limits. Ultrasound of ovaries concurred with the operative report: there was a complete absence of both ovaries. Bone density measurement showed mild osteopenia. Serum estradiol, progesteron, and serum FSH, LH were at menopausal level. Serum testosteron was normal. Serum cortison was low. Serum prolactine was within normal limits. Serum T4 was low, and serum TSH was higher than normal.

The treatment with Premarin 1.25 mg, and Provera 10 mg for 7 days starting on 17th day of cycle, continued, and on 10/18/94 the patient received fetal precursor cell transplantation of ovary, placenta, hypothalamus, liver, adrenal cortex, spleen, anterior lobe of pituitary.

The post-transplantation course was unremarkable. Within 4 weeks the patient observed a reversal of all symptoms. This favorable clinical course was confirmed by the laboratory testing of hormonal levels.

The serum estradiol increased from very low menopausal levels at 1 month to 0.2 nanomol/L, at 2 months to 0.35 nanomol/L, at 4 months to 0.6 nanomol/L (which is the lower limit of normal estradiol level), and then dropped to 0.3 nanomol/L, and stayed at this level for the duration of the first year after cell transplantation.

The level of serum progesteron followed the course of estrogen.

The serum FSH decreased from very high menopausal levels at 1 month to 20 IU/L, at 2 months to 10 IU/L (which is the upper level of normal FSH levels), at 4 months it was at 15 IU/L, at 6 months it increased up to 35 IU/L and remained at this level for the duration of the first year after cell transplantation.

The serum LH decreased from very high menopausal levels at 1 month to 22 IU/L, at 3 months to 10 IU/L (which is within normal limits), at 4 months was 10 IU/L, at 5 months it increased to 20 IU/L, and one year after cell transplantation it was 25 IU/L.

Serum testosteron increased 3 months after cell transplantation, but generally remained within normal limits for the entire one year.

Serum prolactine remained normal for the entire one year after cell transplantation, without much variations.

Serum cortisol increased from subnormal levels within 4 months to high normal levels and then again decreased to the lower limit of normal 8 months after cell transplantation.

Serum TSH dropped from abnormally high levels within a month to the normal level, and remained normal (with slight variations) for the duration of one year after cell transplantation.

After 12 months the patient received the 2nd cell transplantation of the same 7 transplants as before. The laboratory testing of the above described hormones revealed the following.

Serum estradiol reached normal level in 3 months, and remained normal for the duration of the follow-up of 12 months after the second cell transplantation.

Serum progesteron reached normal level in 2 months and remained normal for the duration of the follow-up of 12 months after the second cell transplantation.

Serum FSH reached an upper limit of normal after one month and remained at that level until 8 months after the second cell transplantation, but even afterward did not rise over the level of 20 IU/L.

Serum LH decreased to 25 IU/L in 2 months, and to 15 IU/L in 5 months, and to the normal level at 9 months after the second cell transplantation, and remained like that for the duration of the 12 months of follow-up.

Serum testosteron remained within limits of normal, although it was slowly moving up with a peak at 8 months after the second cell transplantation.

Serum prolactine remained within normal limits for the entire one year after the second cell transplantation.

Serum cortisol reached subnormal levels 12 months after the first cell transplantation, but within 2 months after the second one it was within normal limits again, and it remained so for the duration of follow-up of 12 months.

Serum TSH remained within normal limits after the second cell transplantation.

Overall the 2nd cell transplantation had a more pronounced effect, and significantly prolonged, as all hormone levels proved.