Amenorrhea

Using the knowledge generated in earlier years that the secretion of pituitary gonadotropins is regulated by the gonadotropin-releasing hormone (GnRH) neurons, spectacular advances have been made in the neuroendocrine control of reproductive function in the last decade. The major brain sites involved in regulating sexual behavior and pituitary gonadotropin secretion have been identified, as well as the multiple hormones that regulate those complex functions. Significant work has been done on the localization and biology of the receptors for sex steroids and neurotransmitters. Advances in molecular biology have provided new insights into how the genes for neurotransmitters, neurotransmitter transporters, and neurotransmitter receptors are regulated. The use of gene knockout transgenic animals (10-12) and antisense oligonucleotides have helped understand more clearly the physiological role of specific genes in reproductive function.

The applications of these fundamental discoveries to the understanding and treatment of reproductive diseases in women have been numerous. For example, it has been shown that the deficiency of GnRH secretion in Kallmann's syndrome is frequently due to the failure of embryonic GnRH neurons to migrate to their hypothalamic destination due to a defect in a neural adhesion molecule. The recognition of pulsatility in GnRH secretion and the subsequent discovery that continuous GnRH desensitizes the pituitary has led to treatments with pulsatile GnRH or long-acting GnRH analogs to either stimulate or suppress reproductive function, respectively. The recognition of the importance of secretion of growth factors by glial cells and astrocytes that, in turn, regulates the maturation of the GnRH neurons has led to important advances in understanding the process of normal puberty and the malfunction in precocious puberty (13). Important advances have been made in the understanding of the effect of stress and infections through glucocorticoids, prolactin, corticotropin-releasing hormone (CRH), and cytokines on the GnRH neurons (14) and reproductive function. Furthermore, considerable progress has been made in elucidating the relationship between nutritional status and reproduction. For example, recent studies have demonstrated that the fat cell hormone, leptin, is essential for normal reproductive function, although the mechanisms by which it affects reproduction are unknown (15).

Ovarian follicular development and the process of ovulation and maintenance of the corpus luteum are under the control of pituitary gonadotropins. Hypothalamic-pituitary failure is a major cause of amenorrhea. The regulation of LH secretion is much more tightly coupled with GnRH secretion than is FSH secretion (16, 17). Research in the last decade has clearly established that in addition to GnRH, inhibin, activin, follistatin, progesterone (through its 5-reduction), and glucocorticoids regulate FSH secretion. The regulation of the preovulatory gonadotropin surge leading to ovulation has also been studied extensively during the same time period and has revealed a high degree of unexpected complexity. In addition to estradiol, ovarian and adrenal progesterone have been shown to be essential for the magnitude and duration of the preovulatory LH surge (18). These steroids do not act directly on the GnRH neurons to induce the preovulatory LH surge, but rather influence the release of neuropeptides and neurotransmitters. Increasing LH secretion-stimulating (accelerating) factors and decreasing inhibitory (braking) factors precipitate the LH surge. The list of major accelerating signals for GnRH secretion has expanded and now includes norepinephrine, neuropeptide Y, galanin, and the excitatory amino acid, glutamate, working through N-methyl-D-aspartate (NMDA) and non-NMDA receptors (19-21). Evidence is accumulating which suggests that the novel gaseous transmitter nitric oxide acts to mediate glutamate signals to the GnRH neuron (22). Major inhibitors of GnRH secretion include opioids, GABA, and tackykinins. The enzyme glutamic acid decarboxylase has been shown to be very important in altering the balance between stimulatory (glutamate) and GABA (inhibitory) signals around the time of the LH surge when glutamate levels increase and GABA levels decrease (23).

The premature loss of follicles from the ovary also robs a woman of female sex hormones. This may be the consequence of genetic aberrations that lead to a reduced germ cell population in the fetal ovaries (gonadal dysgenesis), inherited metabolic disease that promotes follicular demise (galactosemia, myotonic dystrophy), autoimmune disorders, and destruction of ovarian tissue as a result of infection or toxic effects of radiation or chemotherapy. Important recent advances include the discovery that the orphan nuclear transcription factor, steroidogenic factor 1, is essential for gonadal development and the demonstration in a Finnish family that mutations in the FSH receptor cause ovarian failure. The latter discovery raises significant questions regarding the role of FSH in ovarian function, which may be addressed by recent animal experiments in which the FSH gene and FSH receptor have been mutated.

Ovarian failure is frequently associated with autoimmune disease affecting other endocrine glands (24). A genetic component to this type of ovarian dysfunction is likely as animal studies suggest the presence of susceptibility and resistance loci. A locus on chromosome 21 has been linked to one form of autoimmune ovarian failure in the Finnish population. However, the way in which these genes interact and how they modify the expression of ovarian determinants and immune cell responses is unknown at the present time. 

Drug Therapies

Your provider may suggest the following drugs:

• Oral contraceptives or hormones to cause menstruation to start
• Estrogen replacement for low levels of estrogen caused by ovarian disorders, hysterectomy, or menopause; greatly reduces risk of cardiovascular disease and inhibits osteoporosis; conjugated estrogens 0.625 to 1.25 mg per day; or on days 1 to 25 of calendar month (0.3 mg per day prevents bone loss). Women with an intact uterus should receive progestin (medroxyprogesterone acetate (MPA), a progestin, is given 5 to 10 mg per day on days 16 to 25 of calendar month to reduce risk of estrogen-induced endometrial cancer)
• Progesterone to treat ovarian cysts and some intrauterine disorders
• Alternative estrogen replacement: includes ethinyl estradiol (20 or 50 mcg); estradiol (0.5, 1, 2 mg); Selective Estrogen Receptor Modulators (SERMs) such as raloxifene if individual refuses estrogen but is at-risk for osteoporosis

Complementary and Alternative Therapies

Alternative therapies may help the body metabolize hormones while ensuring that the nutritional requirements for hormone production are met.

Nutrition

• Calcium (1,000 mg per day), magnesium (600 mg per day), vitamin D (200 to 400 IU per day), vitamin K (1 mg per day), and boron (1 to 3 mg per day).
• Iodine (up to 600 mcg per day), tyrosine (200 mg one to two times per day), zinc (30 mg per day), vitamin E (800 IU per day), vitamin A (10,000 to 15,000 IU per day), vitamin C (250 to 500 mg two times per day), and selenium (200 mcg per day).
• B6 (200 mg per day) may reduce high prolactin levels.
• Essential fatty acids:  (1,000 to 1,500 mg one to two times per day).

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