Menopause

Menopause is the period in the life of women when the ovaries stop producing estrogens, a phenomenon which coincides with a series of natural biological changes in the woman’s body. 

While the secretion of estrogens by the ovaries stops in all women at menopause, the secretion of DHEA, the only source of estrogens and androgens after menopause, has already, starting at the age of about 30 years, decreased by an average of 60% at time of menopause. 

This resulting hormonal deficiency is responsible for a series of symptoms typical of postmenopause which vary from one woman to another. 

The possible symptoms of menopause related to hormone deficiency are: 

  • VulvoVaginal atrophy
  • Sexual dysfunction
  • Hot flushes
  • Osteoporosis
  • Loss of muscle mass
  • Fat accumulation 
  • Type 2 diabetes
  • High cholesterol
  • Skin atrophy
  • Memory loss 
  • Cognition loss

Vulvovaginal Atrophy (VVA)

Menopause occurs at about the age of 50 years when the ovaries stop producing estrogens. The serum DHEA concentration, on the other hand, has already decreased on average by 60% at the time of menopause.

Vulvovaginal atrophy and sexual dysfunction are two problems affecting approximately 50% of postmenopausal women. The clinical studies of Endoceuticsä are based upon the very important discovery by Endoceuticsä that the lack of DHEA is the true cause of the problems of menopause.

The combined hormonal deficiency of both estrogens and androgens results in a thinning of the vaginal wall and a decrease in lubrication. The vaginal mucosa becomes less hydrated and less elastic with dryness and pain at sexual activity.

Contrary to hot flushes which are usually temporary and eventually cease, even in the absence of treatment, the problems associated with vulvovaginal atrophy usually increase with age in the absence of treatment. This menopausal problem can seriously affect quality of life in a large proportion of women, including an increase in vaginal and urinary infections.

Approximately 50% of postmenopausal women suffer from vulvovaginal atrophy, the incidence increasing with age. Despite the symptoms, only about 3% of the affected women seek treatment for short periods of time for various reasons, most commonly because of the fear of potential estrogen-related side effects. Consequently, about 97% of the women who suffer from vulvovaginal atrophy symptoms are left without treatment for a large part of their life.

Symptoms and Signs

Vulvovaginal atrophy results in a thinning of the vaginal wall and a decrease in vaginal lubrication and elasticity. These changes can cause vaginal dryness and important pain during sexual activity. Also known as dyspareunia, the pain varies in intensity from one woman to another. The pain may or may not be accompanied by bleeding at intercourse.

Vulvovaginal atrophy may also result in irritation and itching of variable intensity. Some women suffering from irritation and itching do not necessarily relate it to vulvovaginal atrophy, but rather to an inflammatory reaction, allergy or vaginal infection which can be present in a significant proportion of women.

Vulvovaginal atrophy can also be accompanied by serious complications like bladder and possibly kidney infections.

Current Treatments of Vulvovaginal Atrophy 

While both estrogens and androgens are missing at menopause and continue to decrease thereafter, treatment of the problems related to the hormonal deficiency of menopause have so far been exclusively based upon estrogens. In fact, the treatment of vulvovaginal atrophy has always been limited to estrogens taken orally or applied locally in the vagina.

Endoceuticsä’ Discovery

The data obtained by Endoceuticsä have demonstrated the presence of another very important but so-far unrecognized source of sex steroids in women, namely dehydroepiandrosterone (DHEA), a compound inactive in itself but the precursor of all sex steroids. In fact, after menopause, a time when the secretion of estrogens by the ovaries stops, the only source of estrogens and androgens becomes DHEA which is transformed intracellularly into estrogens and androgens in peripheral target tissues without biologically significant release of active estrogens or androgens in the blood. This achievement is due to the intracellular inactivation of the estrogens and androgens made from DHEA in the same cells where they are synthesized.

DHEA, however, markedly decreases with age and its serum concentrations are highly variable between women, its levels ranging from barely detectable in some women to relatively high values or concentrations similar to those seen before menopause in other women.

Cessation of estrogen secretion by the ovaries at menopause is a normal phenomenon present in all women. Consequently, the biologically inactive concentration of estradiol in the circulation after menopause cannot explain why some women have menopausal symptoms, while others do not suffer from such symptoms. In fact, cessation of estrogen secretion by the ovaries is the same in all women and the serum concentration of estradiol is very low and biologically inactive in all women. Consequently, since DHEA is the exclusive source of sex steroids after menopause, women with high serum DHEA have no or minimal menopausal symptoms, while women with low DHEA suffer from menopausal symptoms: the lack of DHEA is then the cause of the symptoms of menopause.

DHEA is secreted mostly by the adrenal glands into the general circulation which distributes this inactive precursor molecule to all tissues where it is locally transformed into precise and very small quantities of androgens and estrogens which permit a local control of cellular activity according to the local needs. Since the estrogens and androgens made intracellularly from DHEA are degraded locally, only the inactive degradation products are released in the blood for elimination by the liver and kidneys.

Non-estrogenic treatment of vulvovaginal atrophy : Intrarosaä

Endoceuticsä has developed a non-estrogenic treatment for vulvovaginal atrophy. This treatment uses Prasterone (DHEA), a compound without intrinsic estrogenic or androgenic activity which is transformed intracellularly into androgens and estrogens only in the cells and vaginal layers physiologically in need of these sex steroids.This innovative treatment provides a replacement for the local deficiency in sex steroids with no significant increase in circulating estrogens or androgens.

In addition, positive effects are observed on the four domains of sexual dysfunction, namely desire, arousal, orgasm and pleasure, an effect secondary to local androgen formation and not found with estrogens. These observations are under evaluation by Endoceuticsä.

·         The approach discovered by Endoceuticsä is a non-estrogenic treatment for vulvovaginal atrophy and potentially female sexual dysfunction (to be confirmed in future clinical trials.

·         Treatment of vulvovaginal atrophy is thus achieved by a strictly local action in the vagina without exposure of the other tissues to estrogens or androgens.

·         Pre-clinical studies show that Prasterone, through its local conversion into both estrogens and androgens, affects all three layers of the vaginal wall, thus permitting beneficial effects on vulvovaginal atrophy and possibly sexual dysfunction.

DHEA + acolbifene, the Therapeutic Strategy Followed by Endoceuticä for the prevention of osteoporosis.

Endoceuticsä is also focusing its strategy on the combination of DHEA and its own SERM (selective estrogen receptor modulator) acolbifene to relieve the symptoms of menopause without the risk of breast cancer associated with estrogens. In addition, preclinical studies have shown that the combination of both compounds led to important benefits on bone. In fact, DHEA increases bone formation, while acolbifene decreases bone loss. Other positive effects such as a decrease in cholesterol and fat accumulation have also been observed.

The potent inhibitory effect of acolbifene observed on cell proliferation in the mammary gland of women at high risk of breast cancer in a study performed by the US National Cancer Institute and the pure antagonistic activity of acolbifene demonstrated in the human breast and uterine cancer cells strongly support its potential long-term use in women with the high probability of breast and uterine cancer prevention.